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Sample records for randomly selected target

  1. Implications of structural genomics target selection strategies: Pfam5000, whole genome, and random approaches

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Brenner, Steven E.

    2004-07-14

    The structural genomics project is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy which is medically and biologically relevant, of good value, and tractable. As an option to consider, we present the Pfam5000 strategy, which involves selecting the 5000 most important families from the Pfam database as sources for targets. We compare the Pfam5000 strategy to several other proposed strategies that would require similar numbers of targets. These include including complete solution of several small to moderately sized bacterial proteomes, partial coverage of the human proteome, and random selection of approximately 5000 targets from sequenced genomes. We measure the impact that successful implementation of these strategies would have upon structural interpretation of the proteins in Swiss-Prot, TrEMBL, and 131 complete proteomes (including 10 of eukaryotes) from the Proteome Analysis database at EBI. Solving the structures of proteins from the 5000 largest Pfam families would allow accurate fold assignment for approximately 68 percent of all prokaryotic proteins (covering 59 percent of residues) and 61 percent of eukaryotic proteins (40 percent of residues). More fine-grained coverage which would allow accurate modeling of these proteins would require an order of magnitude more targets. The Pfam5000 strategy may be modified in several ways, for example to focus on larger families, bacterial sequences, or eukaryotic sequences; as long as secondary consideration is given to large families within Pfam, coverage results vary only slightly. In contrast, focusing structural genomics on a single tractable genome would have only a limited impact in structural knowledge of other proteomes: a significant fraction (about 30-40 percent of the proteins, and 40-60 percent of the residues) of each proteome is classified in small

  2. Effectiveness of a selective, personality-targeted prevention program for adolescent alcohol use and misuse: a cluster randomized controlled trial.

    Science.gov (United States)

    Conrod, Patricia J; O'Leary-Barrett, Maeve; Newton, Nicola; Topper, Lauren; Castellanos-Ryan, Natalie; Mackie, Clare; Girard, Alain

    2013-03-01

    Selective school-based alcohol prevention programs targeting youth with personality risk factors for addiction and mental health problems have been found to reduce substance use and misuse in those with elevated personality profiles. To report 24-month outcomes of the Teacher-Delivered Personality-Targeted Interventions for Substance Misuse Trial (Adventure trial) in which school staff were trained to provide interventions to students with 1 of 4 high-risk (HR) profiles: anxiety sensitivity, hopelessness, impulsivity, and sensation seeking and to examine the indirect herd effects of this program on the broader low-risk (LR) population of students who were not selected for intervention. Cluster randomized controlled trial. Secondary schools in London, United Kingdom. A total of 1210 HR and 1433 LR students in the ninth grade (mean [SD] age, 13.7 [0.33] years). Schools were randomized to provide brief personality-targeted interventions to HR youth or treatment as usual (statutory drug education in class). Participants were assessed for drinking, binge drinking, and problem drinking before randomization and at 6-monthly intervals for 2 years. Two-part latent growth models indicated long-term effects of the intervention on drinking rates (β = -0.320, SE = 0.145, P = .03) and binge drinking rates (β = -0.400, SE = 0.179, P = .03) and growth in binge drinking (β = -0.716, SE = 0.274, P = .009) and problem drinking (β = -0.452, SE = 0.193, P = .02) for HR youth. The HR youth were also found to benefit from the interventions during the 24-month follow-up on drinking quantity (β = -0.098, SE = 0.047, P = .04), growth in drinking quantity (β = -0.176, SE = 0.073, P = .02), and growth in binge drinking frequency (β = -0.183, SE = 0.092, P = .047). Some herd effects in LR youth were observed, specifically on drinking rates (β = -0.259, SE = 0.132, P = .049) and growth of binge drinking (β = -0.244, SE = 0.073, P = .001), during the 24-month follow-up. Findings further

  3. The Long-Term Effectiveness of a Selective, Personality-Targeted Prevention Program in Reducing Alcohol Use and Related Harms: A Cluster Randomized Controlled Trial

    Science.gov (United States)

    Newton, Nicola C.; Conrod, Patricia J.; Slade, Tim; Carragher, Natacha; Champion, Katrina E.; Barrett, Emma L.; Kelly, Erin V.; Nair, Natasha K.; Stapinski, Lexine; Teesson, Maree

    2016-01-01

    Background: This study investigated the long-term effectiveness of Preventure, a selective personality-targeted prevention program, in reducing the uptake of alcohol, harmful use of alcohol, and alcohol-related harms over a 3-year period. Methods: A cluster randomized controlled trial was conducted to assess the effectiveness of Preventure.…

  4. Burglar Target Selection

    Science.gov (United States)

    Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

    2015-01-01

    Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

  5. Food pantry selection solutions: a randomized controlled trial in client-choice food pantries to nudge clients to targeted foods.

    Science.gov (United States)

    Wilson, Norbert L W; Just, David R; Swigert, Jeffery; Wansink, Brian

    2017-06-01

    Food pantries and food banks are interested in cost-effective methods to encourage the selection of targeted foods without restricting choices. Thus, this study evaluates the effectiveness of nudges toward targeted foods. In October/November 2014, we manipulated the display of a targeted product in a New York State food pantry. We evaluated the binary choice of the targeted good when we placed it in the front or the back of the category line (placement order) and when we presented the product in its original box or unboxed (packaging). The average uptake proportion for the back treatment was 0.231, 95% CI = 0.179, 0.29, n = 205, and for the front treatment, the proportion was 0.337, 95% CI = 0.272, 0.406, n = 238 with an odds ratio of 1.688, 95% CI = 1.088, 2.523. The average uptake for the unboxed treatment was 0.224, 95% CI = 0.174, 0.280, n = 255, and for the boxed intervention, the proportion was 0.356, 95% CI = 0.288, 0.429, n = 188 with an odds ratio of 1.923, 95% CI = 1.237, 2.991. Nudges increased uptake of the targeted food. The findings also hold when we control for a potential confounder. Low cost and unobtrusive nudges can be effective tools for food pantry organizers to encourage the selection of targeted foods. NCT02403882.

  6. Blocked Randomization with Randomly Selected Block Sizes

    Directory of Open Access Journals (Sweden)

    Jimmy Efird

    2010-12-01

    Full Text Available When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes.

  7. Blocked randomization with randomly selected block sizes.

    Science.gov (United States)

    Efird, Jimmy

    2011-01-01

    When planning a randomized clinical trial, careful consideration must be given to how participants are selected for various arms of a study. Selection and accidental bias may occur when participants are not assigned to study groups with equal probability. A simple random allocation scheme is a process by which each participant has equal likelihood of being assigned to treatment versus referent groups. However, by chance an unequal number of individuals may be assigned to each arm of the study and thus decrease the power to detect statistically significant differences between groups. Block randomization is a commonly used technique in clinical trial design to reduce bias and achieve balance in the allocation of participants to treatment arms, especially when the sample size is small. This method increases the probability that each arm will contain an equal number of individuals by sequencing participant assignments by block. Yet still, the allocation process may be predictable, for example, when the investigator is not blind and the block size is fixed. This paper provides an overview of blocked randomization and illustrates how to avoid selection bias by using random block sizes.

  8. Randomized selection on the GPU

    Energy Technology Data Exchange (ETDEWEB)

    Monroe, Laura Marie [Los Alamos National Laboratory; Wendelberger, Joanne R [Los Alamos National Laboratory; Michalak, Sarah E [Los Alamos National Laboratory

    2011-01-13

    We implement here a fast and memory-sparing probabilistic top N selection algorithm on the GPU. To our knowledge, this is the first direct selection in the literature for the GPU. The algorithm proceeds via a probabilistic-guess-and-chcck process searching for the Nth element. It always gives a correct result and always terminates. The use of randomization reduces the amount of data that needs heavy processing, and so reduces the average time required for the algorithm. Probabilistic Las Vegas algorithms of this kind are a form of stochastic optimization and can be well suited to more general parallel processors with limited amounts of fast memory.

  9. Random selection of Borel sets

    Directory of Open Access Journals (Sweden)

    Bernd Günther

    2010-10-01

    Full Text Available A theory of random Borel sets is presented, based on dyadic resolutions of compact metric spaces. The conditional expectation of the intersection of two independent random Borel sets is investigated. An example based on an embedding of Sierpinski’s universal curve into the space of Borel sets is given.

  10. Target selection for direct marketing.

    NARCIS (Netherlands)

    Bult, Jan Roelf

    1993-01-01

    In this thesis we concentrated on the use ol direct mail for targeting potential buyers. The major characteristics that influences the success of a plomotional direct mail campaign are the of-fbr,the communication elements, the timing or sequence of these communication elements, and the list of

  11. Effectiveness of a selective intervention program targeting personality risk factors for alcohol misuse among young adolescents: results of a cluster randomized controlled trial

    NARCIS (Netherlands)

    Lammers, J.; Goossens, F.; Conrod, P.; Engels, R.; Wiers, R.W.; Kleinjan, M.

    2015-01-01

    Aim: The effectiveness of Preventure was tested on drinking behaviour of young adolescents in secondary education in the Netherlands. Design: A cluster randomized controlled trial was carried out, with participants assigned randomly to a two-session coping skills intervention or a control

  12. Peptide Selection for Targeted Protein Quantitation.

    Science.gov (United States)

    Chiva, Cristina; Sabidó, Eduard

    2017-03-03

    Targeted proteomics methods in their different flavors rely on the use of a few peptides as proxies for protein quantitation, which need to be specified either prior to or after data acquisition. However, in contrast with discovery methods that use all identified peptides for a given protein to estimate its abundance, targeted proteomics methods are limited in the number of peptides that are used for protein quantitation. Because only a few peptides per protein are acquired or extracted in targeted experiments, the selection of peptides that are used for targeted protein quantitation becomes crucial. Several rules have been proposed to guide peptide selection for targeted proteomics studies, which have generally been based on the amino acidic composition of the peptide sequences. However, the compliance of these rules does not imply that not-conformed peptides are not reproducibly generated nor do they guarantee that the selected peptides correctly represent the behavior of the protein abundance under different conditions.

  13. Selective targeting of epigenetic reader domains.

    Science.gov (United States)

    Greschik, Holger; Schüle, Roland; Günther, Thomas

    2017-05-01

    Epigenetic regulators including writers, erasers, and readers of chromatin marks have been implicated in numerous diseases and are therefore subject of intense academic and pharmaceutical research. While several small-molecule inhibitors targeting writers or erasers are either approved drugs or are currently being evaluated in clinical trials, the targeting of epigenetic readers has lagged behind. Proof-of-principle that epigenetic readers are also relevant drug targets was provided by landmark discoveries of selective inhibitors targeting the BET family of acetyl-lysine readers. More recently, high affinity chemical probes for non-BET acetyl- and methyl-lysine reader domains have also been developed. Areas covered: This article covers recent advances with the identification and validation of inhibitors and chemical probes targeting epigenetic reader domains. Issues related to epigenetic reader druggability, quality requirements for chemical probes, interpretation of cellular action, unexpected cross-talk, and future challenges are also discussed. Expert opinion: Chemical probes provide a powerful means to unravel biological functions of epigenetic readers and evaluate their potential as drug targets. To yield meaningful results, potency, selectivity, and cellular target engagement of chemical probes need to be stringently validated. Future chemical probes will probably need to fulfil additional criteria such as strict target specificity or the targeting of readers within protein complexes.

  14. Microsatellites as targets of natural selection.

    Science.gov (United States)

    Haasl, Ryan J; Payseur, Bret A

    2013-02-01

    The ability to survey polymorphism on a genomic scale has enabled genome-wide scans for the targets of natural selection. Theory that connects patterns of genetic variation to evidence of natural selection most often assumes a diallelic locus and no recurrent mutation. Although these assumptions are suitable to selection that targets single nucleotide variants, fundamentally different types of mutation generate abundant polymorphism in genomes. Moreover, recent empirical results suggest that mutationally complex, multiallelic loci including microsatellites and copy number variants are sometimes targeted by natural selection. Given their abundance, the lack of inference methods tailored to the mutational peculiarities of these types of loci represents a notable gap in our ability to interrogate genomes for signatures of natural selection. Previous theoretical investigations of mutation-selection balance at multiallelic loci include assumptions that limit their application to inference from empirical data. Focusing on microsatellites, we assess the dynamics and population-level consequences of selection targeting mutationally complex variants. We develop general models of a multiallelic fitness surface, a realistic model of microsatellite mutation, and an efficient simulation algorithm. Using these tools, we explore mutation-selection-drift equilibrium at microsatellites and investigate the mutational history and selective regime of the microsatellite that causes Friedreich's ataxia. We characterize microsatellite selective events by their duration and cost, note similarities to sweeps from standing point variation, and conclude that it is premature to label microsatellites as ubiquitous agents of efficient adaptive change. Together, our models and simulation algorithm provide a powerful framework for statistical inference, which can be used to test the neutrality of microsatellites and other multiallelic variants.

  15. Efficient target-selected mutagenesis in zebrafish

    NARCIS (Netherlands)

    Wienholds, E.; van Eeden, F.; Kosters, M.; Mudde, J.B.; Plasterk, R.; Cuppen, E.

    2003-01-01

    One of the most powerful methods available to assign function to a gene is to inactivate or knockout the gene. Recently,we described the first target-selected knockout in zebrafish. Here,we report on the further improvements of this procedure,resulting in a highly efficient and easy method to do

  16. Species selection and random drift in macroevolution.

    Science.gov (United States)

    Chevin, Luis-Miguel

    2016-03-01

    Species selection resulting from trait-dependent speciation and extinction is increasingly recognized as an important mechanism of phenotypic macroevolution. However, the recent bloom in statistical methods quantifying this process faces a scarcity of dynamical theory for their interpretation, notably regarding the relative contributions of deterministic versus stochastic evolutionary forces. I use simple diffusion approximations of birth-death processes to investigate how the expected and random components of macroevolutionary change depend on phenotype-dependent speciation and extinction rates, as can be estimated empirically. I show that the species selection coefficient for a binary trait, and selection differential for a quantitative trait, depend not only on differences in net diversification rates (speciation minus extinction), but also on differences in species turnover rates (speciation plus extinction), especially in small clades. The randomness in speciation and extinction events also produces a species-level equivalent to random genetic drift, which is stronger for higher turnover rates. I then show how microevolutionary processes including mutation, organismic selection, and random genetic drift cause state transitions at the species level, allowing comparison of evolutionary forces across levels. A key parameter that would be needed to apply this theory is the distribution and rate of origination of new optimum phenotypes along a phylogeny. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

  17. RFMirTarget: predicting human microRNA target genes with a random forest classifier.

    Directory of Open Access Journals (Sweden)

    Mariana R Mendoza

    Full Text Available MicroRNAs are key regulators of eukaryotic gene expression whose fundamental role has already been identified in many cell pathways. The correct identification of miRNAs targets is still a major challenge in bioinformatics and has motivated the development of several computational methods to overcome inherent limitations of experimental analysis. Indeed, the best results reported so far in terms of specificity and sensitivity are associated to machine learning-based methods for microRNA-target prediction. Following this trend, in the current paper we discuss and explore a microRNA-target prediction method based on a random forest classifier, namely RFMirTarget. Despite its well-known robustness regarding general classifying tasks, to the best of our knowledge, random forest have not been deeply explored for the specific context of predicting microRNAs targets. Our framework first analyzes alignments between candidate microRNA-target pairs and extracts a set of structural, thermodynamics, alignment, seed and position-based features, upon which classification is performed. Experiments have shown that RFMirTarget outperforms several well-known classifiers with statistical significance, and that its performance is not impaired by the class imbalance problem or features correlation. Moreover, comparing it against other algorithms for microRNA target prediction using independent test data sets from TarBase and starBase, we observe a very promising performance, with higher sensitivity in relation to other methods. Finally, tests performed with RFMirTarget show the benefits of feature selection even for a classifier with embedded feature importance analysis, and the consistency between relevant features identified and important biological properties for effective microRNA-target gene alignment.

  18. Improving randomness characterization through Bayesian model selection.

    Science.gov (United States)

    Díaz Hernández Rojas, Rafael; Solís, Aldo; Angulo Martínez, Alí M; U'Ren, Alfred B; Hirsch, Jorge G; Marsili, Matteo; Pérez Castillo, Isaac

    2017-06-08

    Random number generation plays an essential role in technology with important applications in areas ranging from cryptography to Monte Carlo methods, and other probabilistic algorithms. All such applications require high-quality sources of random numbers, yet effective methods for assessing whether a source produce truly random sequences are still missing. Current methods either do not rely on a formal description of randomness (NIST test suite) on the one hand, or are inapplicable in principle (the characterization derived from the Algorithmic Theory of Information), on the other, for they require testing all the possible computer programs that could produce the sequence to be analysed. Here we present a rigorous method that overcomes these problems based on Bayesian model selection. We derive analytic expressions for a model's likelihood which is then used to compute its posterior distribution. Our method proves to be more rigorous than NIST's suite and Borel-Normality criterion and its implementation is straightforward. We applied our method to an experimental device based on the process of spontaneous parametric downconversion to confirm it behaves as a genuine quantum random number generator. As our approach relies on Bayesian inference our scheme transcends individual sequence analysis, leading to a characterization of the source itself.

  19. Target selection for structural genomics: an overview.

    Science.gov (United States)

    Marsden, Russell L; Orengo, Christine A

    2008-01-01

    The success of the whole genome sequencing projects brought considerable credence to the belief that high-throughput approaches, rather than traditional hypothesis-driven research, would be essential to structurally and functionally annotate the rapid growth in available sequence data within a reasonable time frame. Such observations supported the emerging field of structural genomics, which is now faced with the task of providing a library of protein structures that represent the biological diversity of the protein universe. To run efficiently, structural genomics projects aim to define a set of targets that maximize the potential of each structure discovery whether it represents a novel structure, novel function, or missing evolutionary link. However, not all protein sequences make suitable structural genomics targets: It takes considerably more effort to determine the structure of a protein than the sequence of its gene because of the increased complexity of the methods involved and also because the behavior of targeted proteins can be extremely variable at the different stages in the structural genomics "pipeline." Therefore, structural genomics target selection must identify and prioritize the most suitable candidate proteins for structure determination, avoiding "problematic" proteins while also ensuring the ultimate goals of the project are followed.

  20. 32 CFR 1624.1 - Random selection procedures for induction.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Random selection procedures for induction. 1624... SYSTEM INDUCTIONS § 1624.1 Random selection procedures for induction. (a) The Director of Selective Service shall from time to time establish a random selection sequence for induction by a drawing to be...

  1. Variational data assimilation using targetted random walks

    KAUST Repository

    Cotter, S. L.

    2011-02-15

    The variational approach to data assimilation is a widely used methodology for both online prediction and for reanalysis. In either of these scenarios, it can be important to assess uncertainties in the assimilated state. Ideally, it is desirable to have complete information concerning the Bayesian posterior distribution for unknown state given data. We show that complete computational probing of this posterior distribution is now within the reach in the offline situation. We introduce a Markov chain-Monte Carlo (MCMC) method which enables us to directly sample from the Bayesian posterior distribution on the unknown functions of interest given observations. Since we are aware that these methods are currently too computationally expensive to consider using in an online filtering scenario, we frame this in the context of offline reanalysis. Using a simple random walk-type MCMC method, we are able to characterize the posterior distribution using only evaluations of the forward model of the problem, and of the model and data mismatch. No adjoint model is required for the method we use; however, more sophisticated MCMC methods are available which exploit derivative information. For simplicity of exposition, we consider the problem of assimilating data, either Eulerian or Lagrangian, into a low Reynolds number flow in a two-dimensional periodic geometry. We will show that in many cases it is possible to recover the initial condition and model error (which we describe as unknown forcing to the model) from data, and that with increasing amounts of informative data, the uncertainty in our estimations reduces. © 2011 John Wiley & Sons, Ltd.

  2. Selective CFAE targeting for atrial fibrillation study (SELECT AF): clinical rationale, design, and implementation.

    Science.gov (United States)

    Verma, Atul; Sanders, Prashanthan; Macle, Laurent; Champagne, Jean; Nair, Girish M; Calkins, Hugh; Wilber, David J

    2011-05-01

    Adjuvant ablation of complex fractionated atrial electrograms (CFAE) in addition to pulmonary vein isolation (PVI) likely improves procedural outcome compared to PVI alone, particularly in patients with persistent atrial fibrillation (AF). However, CFAE regions can be extensive, occasionally requiring a large amount of extra ablation. Some CFAE regions may also represent passive wavefront collision and may not require ablation. Thus, there is interest in identifying more selective CFAE sites that are critical to AF perpetuation, minimizing the amount of adjuvant ablation that must be performed. The SELECT AF study is a prospective, multicenter, randomized trial comparing a strategy of PVI plus generalized CFAE ablation versus a strategy of PVI plus selective CFAE ablation, focusing on regions of continuous electrical activity (CEA). The primary efficacy endpoint is freedom from atrial arrhythmia at 1 year and the primary safety endpoint is total radiofrequency (RF) delivery time per procedure. Patients undergoing a first time ablation procedure for symptomatic persistent AF will be included. Patients with permanent AF or with left atrial size ≥55 mm will be excluded. Patients will all receive PVI at the time of their ablation, but will be randomized 1:1 to receive adjuvant CFAE ablation using the traditional "generalized" approach, or a "selective" approach targeting only CEA regions. Both strategies will be guided by automated mapping algorithms. This study will enroll a minimum of 80 evaluable subjects; 40 in each randomization group. SELECT AF is a randomized trial in patients with persistent AF to evaluate the efficacy of selective versus generalized CFAE ablation in addition to traditional PVI. © 2010 Wiley Periodicals, Inc.

  3. Optimal intermittence in search strategies under speed-selective target detection.

    Science.gov (United States)

    Campos, Daniel; Méndez, Vicenç; Bartumeus, Frederic

    2012-01-13

    Random search theory has been previously explored for both continuous and intermittent scanning modes with full target detection capacity. Here we present a new class of random search problems in which a single searcher performs flights of random velocities, the detection probability when it passes over a target location being conditioned to the searcher speed. As a result, target detection involves an N-passage process for which the mean search time is here analytically obtained through a renewal approximation. We apply the idea of speed-selective detection to random animal foraging since a fast movement is known to significantly degrade perception abilities in many animals. We show that speed-selective detection naturally introduces an optimal level of behavioral intermittence in order to solve the compromise between fast relocations and target detection capability.

  4. Saccade target selection in Chinese reading.

    Science.gov (United States)

    Li, Xingshan; Liu, Pingping; Rayner, Keith

    2015-04-01

    In Chinese reading, there are no spaces to mark the word boundaries, so Chinese readers cannot target their saccades to the center of a word. In this study, we investigated how Chinese readers decide where to move their eyes during reading. To do so, we introduced a variant of the boundary paradigm in which only the target stimulus remained on the screen, displayed at the saccade landing site, after the participant's eyes crossed an invisible boundary. We found that when the saccade target was a word, reaction times in a lexical decision task were shorter when the saccade landing position was closer to the end of that word. These results are consistent with the predictions of a processing-based strategy to determine where to move the eyes. Specifically, this hypothesis assumes that Chinese readers estimate how much information is processed in parafoveal vision and saccade to a location that will carry novel information.

  5. Recombinant protein expression by targeting pre-selected chromosomal loci

    Directory of Open Access Journals (Sweden)

    Krömer Wolfgang

    2009-12-01

    Full Text Available Abstract Background Recombinant protein expression in mammalian cells is mostly achieved by stable integration of transgenes into the chromosomal DNA of established cell lines. The chromosomal surroundings have strong influences on the expression of transgenes. The exploitation of defined loci by targeting expression constructs with different regulatory elements is an approach to design high level expression systems. Further, this allows to evaluate the impact of chromosomal surroundings on distinct vector constructs. Results We explored antibody expression upon targeting diverse expression constructs into previously tagged loci in CHO-K1 and HEK293 cells that exhibit high reporter gene expression. These loci were selected by random transfer of reporter cassettes and subsequent screening. Both, retroviral infection and plasmid transfection with eGFP or antibody expression cassettes were employed for tagging. The tagged cell clones were screened for expression and single copy integration. Cell clones producing > 20 pg/cell in 24 hours could be identified. Selected integration sites that had been flanked with heterologous recombinase target sites (FRTs were targeted by Flp recombinase mediated cassette exchange (RMCE. The results give proof of principle for consistent protein expression upon RMCE. Upon targeting antibody expression cassettes 90-100% of all resulting cell clones showed correct integration. Antibody production was found to be highly consistent within the individual cell clones as expected from their isogenic nature. However, the nature and orientation of expression control elements revealed to be critical. The impact of different promoters was examined with the tag-and-targeting approach. For each of the chosen promoters high expression sites were identified. However, each site supported the chosen promoters to a different extent, indicating that the strength of a particular promoter is dominantly defined by its chromosomal context

  6. A cluster-randomized controlled trial evaluating the effects of delaying onset of adolescent substance abuse on cognitive development and addiction following a selective, personality-targeted intervention programme: the Co-Venture trial.

    Science.gov (United States)

    O'Leary-Barrett, Maeve; Mâsse, Benoit; Pihl, Robert O; Stewart, Sherry H; Séguin, Jean R; Conrod, Patricia J

    2017-10-01

    Substance use and binge drinking during early adolescence are associated with neurocognitive abnormalities, mental health problems and an increased risk for future addiction. The trial aims to evaluate the protective effects of an evidence-based substance use prevention programme on the onset of alcohol and drug use in adolescence, as well as on cognitive, mental health and addiction outcomes over 5 years. Thirty-eight high schools will be recruited, with a final sample of 31 schools assigned to intervention or control conditions (3826 youth). Brief personality-targeted interventions will be delivered to high-risk youth attending intervention schools during the first year of the trial. Control school participants will receive no intervention above what is offered to them in the regular curriculum by their respective schools. Public/private French and English high schools in Montreal (Canada). All grade 7 students (12-13 years old) will be invited to participate. High-risk youth will be identified as those scoring one standard deviation or more above the school mean on one of the four personality subscales of the Substance Use Risk Profile Scale (40-45% youth). Self-reported substance use and mental health symptoms and cognitive functioning measured annually throughout 5 years. Primary outcomes are the onset of substance use disorders at 4 years post-intervention (year 5). Secondary intermediate outcomes are the onset of alcohol and substance use 2 years post-intervention and neuropsychological functions; namely, the protective effects of substance use prevention on cognitive functions generally, and executive functions and reward sensitivity specifically. This longitudinal, cluster-randomized controlled trial will investigate the impact of a brief personality-targeted intervention program on reducing the onset of addiction 4 years-post intervention. Results will tease apart the developmental sequences of uptake and growth in substance use and cognitive

  7. Sexual selection targets cetacean pelvic bones

    Science.gov (United States)

    Dines, J. P.; Otárola-Castillo, E.; Ralph, P.; Alas, J.; Daley, T.; Smith, A. D.; Dean, M. D.

    2014-01-01

    Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis which seems to serve no other function except to anchor muscles that maneuver the penis. Here we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: 1) males from species with relatively intense sexual selection (inferred by relative testes size) have evolved relatively large penises and pelvic bones compared to their body size, and 2) pelvic bone shape diverges more quickly in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. PMID:25186496

  8. Sexual selection targets cetacean pelvic bones.

    Science.gov (United States)

    Dines, James P; Otárola-Castillo, Erik; Ralph, Peter; Alas, Jesse; Daley, Timothy; Smith, Andrew D; Dean, Matthew D

    2014-11-01

    Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis that seems to serve no other function except to anchor muscles that maneuver the penis. Here, we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: (1) males from species with relatively intense sexual selection (inferred by relative testes size) tend to evolve larger penises and pelvic bones compared to their body length, and (2) pelvic bone shape has diverged more in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  9. In-Place Randomized Slope Selection

    DEFF Research Database (Denmark)

    Blunck, Henrik; Vahrenhold, Jan

    2006-01-01

    Slope selection is a well-known algorithmic tool used in the context of computing robust estimators for fitting a line to a collection P of n points in the plane. We demonstrate that it is possible to perform slope selection in expected O(nlogn) time using only constant extra space in addition to...

  10. Random effect selection in generalised linear models

    DEFF Research Database (Denmark)

    Denwood, Matt; Houe, Hans; Forkman, Björn

    We analysed abattoir recordings of meat inspection codes with possible relevance to onfarm animal welfare in cattle. Random effects logistic regression models were used to describe individual-level data obtained from 461,406 cattle slaughtered in Denmark. Our results demonstrate that the largest ...

  11. Robustness of Dengue Complex Network under Targeted versus Random Attack

    Directory of Open Access Journals (Sweden)

    Hafiz Abid Mahmood Malik

    2017-01-01

    Full Text Available Dengue virus infection is one of those epidemic diseases that require much consideration in order to save the humankind from its unsafe impacts. According to the World Health Organization (WHO, 3.6 billion individuals are at risk because of the dengue virus sickness. Researchers are striving to comprehend the dengue threat. This study is a little commitment to those endeavors. To observe the robustness of the dengue network, we uprooted the links between nodes randomly and targeted by utilizing different centrality measures. The outcomes demonstrated that 5% targeted attack is equivalent to the result of 65% random assault, which showed the topology of this complex network validated a scale-free network instead of random network. Four centrality measures (Degree, Closeness, Betweenness, and Eigenvector have been ascertained to look for focal hubs. It has been observed through the results in this study that robustness of a node and links depends on topology of the network. The dengue epidemic network presented robust behaviour under random attack, and this network turned out to be more vulnerable when the hubs of higher degree have higher probability to fail. Moreover, representation of this network has been projected, and hub removal impact has been shown on the real map of Gombak (Malaysia.

  12. Sequential selection of random vectors under a sum constraint

    OpenAIRE

    Stanke, Mario

    2004-01-01

    We observe a sequence X1,X2,...,Xn of independent and identically distributed coordinatewise nonnegative d-dimensional random vectors. When a vector is observed it can either be selected or rejected but once made this decision is final. In each coordinate the sum of the selected vectors must not exceed a given constant. The problem is to find a selection policy that maximizes the expected number of selected vectors. For a general absolutely continuous distribution of t...

  13. Selectivity and sparseness in randomly connected balanced networks.

    Directory of Open Access Journals (Sweden)

    Cengiz Pehlevan

    Full Text Available Neurons in sensory cortex show stimulus selectivity and sparse population response, even in cases where no strong functionally specific structure in connectivity can be detected. This raises the question whether selectivity and sparseness can be generated and maintained in randomly connected networks. We consider a recurrent network of excitatory and inhibitory spiking neurons with random connectivity, driven by random projections from an input layer of stimulus selective neurons. In this architecture, the stimulus-to-stimulus and neuron-to-neuron modulation of total synaptic input is weak compared to the mean input. Surprisingly, we show that in the balanced state the network can still support high stimulus selectivity and sparse population response. In the balanced state, strong synapses amplify the variation in synaptic input and recurrent inhibition cancels the mean. Functional specificity in connectivity emerges due to the inhomogeneity caused by the generative statistical rule used to build the network. We further elucidate the mechanism behind and evaluate the effects of model parameters on population sparseness and stimulus selectivity. Network response to mixtures of stimuli is investigated. It is shown that a balanced state with unselective inhibition can be achieved with densely connected input to inhibitory population. Balanced networks exhibit the "paradoxical" effect: an increase in excitatory drive to inhibition leads to decreased inhibitory population firing rate. We compare and contrast selectivity and sparseness generated by the balanced network to randomly connected unbalanced networks. Finally, we discuss our results in light of experiments.

  14. In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

    Directory of Open Access Journals (Sweden)

    Ifedayo Victor Ogungbe

    2013-07-01

    Full Text Available Neglected Tropical Diseases (NTDs, like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.

  15. Feature Extraction and Selection Strategies for Automated Target Recognition

    Science.gov (United States)

    Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

    2010-01-01

    Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

  16. Target Selection and Determination of Function in Structural Genomics

    Science.gov (United States)

    Watson, James D.; Todd, Annabel E.; Bray, James; Laskowski, Roman A.; Edwards, Aled; Joachimiak, Andrzej; Orengo, Christine A.; Thornton, Janet M.

    2011-01-01

    Summary The first crucial step in any structural genomics project is the selection and prioritization of target proteins for structure determination. There may be a number of selection criteria to be satisfied, including that the proteins have novel folds, that they be representatives of large families for which no structure is known, and so on. The better the selection at this stage, the greater is the value of the structures obtained at the end of the experimental process. This value can be further enhanced once the protein structures have been solved if the functions of the given proteins can also be determined. Here we describe the methods used at either end of the experimental process: firstly, sensitive sequence comparison techniques for selecting a high-quality list of target proteins, and secondly the various computational methods that can be applied to the eventual 3D structures to determine the most likely biochemical function of the proteins in question. PMID:12880206

  17. Robust Ground Target Detection by SAR and IR Sensor Fusion Using Adaboost-Based Feature Selection

    Directory of Open Access Journals (Sweden)

    Sungho Kim

    2016-07-01

    Full Text Available Long-range ground targets are difficult to detect in a noisy cluttered environment using either synthetic aperture radar (SAR images or infrared (IR images. SAR-based detectors can provide a high detection rate with a high false alarm rate to background scatter noise. IR-based approaches can detect hot targets but are affected strongly by the weather conditions. This paper proposes a novel target detection method by decision-level SAR and IR fusion using an Adaboost-based machine learning scheme to achieve a high detection rate and low false alarm rate. The proposed method consists of individual detection, registration, and fusion architecture. This paper presents a single framework of a SAR and IR target detection method using modified Boolean map visual theory (modBMVT and feature-selection based fusion. Previous methods applied different algorithms to detect SAR and IR targets because of the different physical image characteristics. One method that is optimized for IR target detection produces unsuccessful results in SAR target detection. This study examined the image characteristics and proposed a unified SAR and IR target detection method by inserting a median local average filter (MLAF, pre-filter and an asymmetric morphological closing filter (AMCF, post-filter into the BMVT. The original BMVT was optimized to detect small infrared targets. The proposed modBMVT can remove the thermal and scatter noise by the MLAF and detect extended targets by attaching the AMCF after the BMVT. Heterogeneous SAR and IR images were registered automatically using the proposed RANdom SAmple Region Consensus (RANSARC-based homography optimization after a brute-force correspondence search using the detected target centers and regions. The final targets were detected by feature-selection based sensor fusion using Adaboost. The proposed method showed good SAR and IR target detection performance through feature selection-based decision fusion on a synthetic

  18. WFIRST: Exoplanet Target Selection and Scheduling with Greedy Optimization

    Science.gov (United States)

    Keithly, Dean; Garrett, Daniel; Delacroix, Christian; Savransky, Dmitry

    2018-01-01

    We present target selection and scheduling algorithms for missions with direct imaging of exoplanets, and the Wide Field Infrared Survey Telescope (WFIRST) in particular, which will be equipped with a coronagraphic instrument (CGI). Optimal scheduling of CGI targets can maximize the expected value of directly imaged exoplanets (completeness). Using target completeness as a reward metric and integration time plus overhead time as a cost metric, we can maximize the sum completeness for a mission with a fixed duration. We optimize over these metrics to create a list of target stars using a greedy optimization algorithm based off altruistic yield optimization (AYO) under ideal conditions. We simulate full missions using EXOSIMS by observing targets in this list for their predetermined integration times. In this poster, we report the theoretical maximum sum completeness, mean number of detected exoplanets from Monte Carlo simulations, and the ideal expected value of the simulated missions.

  19. Deep Brain Stimulation Target Selection for Parkinson's Disease.

    Science.gov (United States)

    Honey, Christopher R; Hamani, Clement; Kalia, Suneil K; Sankar, Tejas; Picillo, Marina; Munhoz, Renato P; Fasano, Alfonso; Panisset, Michel

    2017-01-01

    During the "DBS Canada Day" symposium held in Toronto July 4-5, 2014, the scientific committee invited experts to discuss three main questions on target selection for deep brain stimulation (DBS) of patients with Parkinson's disease (PD). First, is the subthalamic nucleus (STN) or the globus pallidus internus (GPi) the ideal target? In summary, both targets are equally effective in improving the motor symptoms of PD. STN allows a greater medications reduction, while GPi exerts a direct antidyskinetic effect. Second, are there further potential targets? Ventral intermediate nucleus DBS has significant long-term benefit for tremor control but insufficiently addresses other motor features of PD. DBS in the posterior subthalamic area also reduces tremor. The pedunculopontine nucleus remains an investigational target. Third, should DBS for PD be performed unilaterally, bilaterally or staged? Unilateral STN DBS can be proposed to asymmetric patients. There is no evidence that a staged bilateral approach reduces the incidence of DBS-related adverse events.

  20. Adverse selection in a community-based health insurance scheme in rural Africa: implications for introducing targeted subsidies.

    Science.gov (United States)

    Parmar, Divya; Souares, Aurélia; de Allegri, Manuela; Savadogo, Germain; Sauerborn, Rainer

    2012-06-28

    Although most community-based health insurance (CBHI) schemes are voluntary, problem of adverse selection is hardly studied. Evidence on the impact of targeted subsidies on adverse selection is completely missing. This paper investigates adverse selection in a CBHI scheme in Burkina Faso. First, we studied the change in adverse selection over a period of 4 years. Second, we studied the effect of targeted subsidies on adverse selection. The study area, covering 41 villages and 1 town, was divided into 33 clusters and CBHI was randomly offered to these clusters during 2004-06. In 2007, premium subsidies were offered to the poor households. The data was collected by a household panel survey 2004-2007 from randomly selected households in these 33 clusters (n = 6795). We applied fixed effect models. We found weak evidence of adverse selection before the implementation of subsidies. Adverse selection significantly increased the next year and targeted subsidies largely explained this increase. Adverse selection is an important concern for any voluntary health insurance scheme. Targeted subsidies are often used as a tool to pursue the vision of universal coverage. At the same time targeted subsidies are also associated with increased adverse selection as found in this study. Therefore, it's essential that targeted subsidies for poor (or other high-risk groups) must be accompanied with a sound plan to bridge the financial gap due to adverse selection so that these schemes can continue to serve these populations.

  1. Peptide-Directed Highly Selective Targeting of Pulmonary Arterial Hypertension

    Science.gov (United States)

    Urakami, Takeo; Järvinen, Tero A.H.; Toba, Michie; Sawada, Junko; Ambalavanan, Namasivayam; Mann, David; McMurtry, Ivan; Oka, Masahiko; Ruoslahti, Erkki; Komatsu, Masanobu

    2011-01-01

    Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary vasculature associated with elevated pulmonary vascular resistance. Despite recent advances in the treatment of PAH, with eight approved clinical therapies and additional therapies undergoing clinical trials, PAH remains a serious life-threatening condition. The lack of pulmonary vascular selectivity and associated systemic adverse effects of these therapies remain the main obstacles to successful treatment. Peptide-mediated drug delivery that specifically targets the vasculature of PAH lungs may offer a solution to the lack of drug selectivity. Herein, we show highly selective targeting of rat PAH lesions by a novel cyclic peptide, CARSKNKDC (CAR). Intravenous administration of CAR peptide resulted in intense accumulation of the peptide in monocrotaline-induced and SU5416/hypoxia-induced hypertensive lungs but not in healthy lungs or other organs of PAH rats. CAR homed to all layers of remodeled pulmonary arteries, ie, endothelium, neointima, medial smooth muscle, and adventitia, in the hypertensive lungs. CAR also homed to capillary vessels and accumulated in the interstitial space of the PAH lungs, manifesting its extravasation activity. These results demonstrated the remarkable ability of CAR to selectively target PAH lung vasculature and effectively penetrate and spread throughout the diseased lung tissue. These results suggest the clinical utility of CAR in the targeted delivery of therapeutic compounds and imaging probes to PAH lungs. PMID:21549345

  2. Classification and Target Group Selection Based Upon Frequent Patterns

    NARCIS (Netherlands)

    W.H.L.M. Pijls (Wim); R. Potharst (Rob)

    2000-01-01

    textabstractIn this technical report , two new algorithms based upon frequent patterns are proposed. One algorithm is a classification method. The other one is an algorithm for target group selection. In both algorithms, first of all, the collection of frequent patterns in the training set is

  3. Fast, Randomized Join-Order Selection - Why Use Transformations?

    NARCIS (Netherlands)

    C.A. Galindo-Legaria; A.J. Pellenkoft (Jan); M.L. Kersten (Martin)

    1994-01-01

    textabstractWe study the effectiveness of probabilistic selection of join-query evaluation plans, without reliance on tree transformation rules. Instead, each candidate plan is chosen uniformly at random from the space of valid evaluation orders. This leads to a transformation-free strategy where a

  4. The reliability of randomly selected final year pharmacy students in ...

    African Journals Online (AJOL)

    Employing ANOVA, factorial experimental analysis, and the theory of error, reliability studies were conducted on the assessment of the drug product chloroquine phosphate tablets. The G–Study employed equal numbers of the factors for uniform control, and involved three analysts (randomly selected final year Pharmacy ...

  5. Competitive interaction degrades target selection: an ERP study.

    Science.gov (United States)

    Hilimire, Matthew R; Mounts, Jeffrey R W; Parks, Nathan A; Corballis, Paul M

    2009-09-01

    Localized attentional interference (LAI) occurs when attending to a visual object degrades processing of nearby objects. Competitive interaction accounts of LAI explain the phenomenon as the result of competition among objects for representation in extrastriate cortex. Here, we examined the N2pc component of the event-related potential (ERP) as a likely neural correlate of LAI. In Experiment 1, participants responded to the orientation of a target while ignoring a nearby decoy. At small target-decoy separations, N2pc amplitude was attenuated whereas the amplitude of a later, positive component (Ptc) was potentiated. Experiment 2 ruled out sensory explanations of these effects. The N2pc results are consistent with the idea that spatially mediated competition for representation in extrastriate cortex degrades target selection. Moreover, the Ptc may reflect a bias signal needed to resolve the competition at smaller target-decoy separations.

  6. Predicting selective drug targets in cancer through metabolic networks

    Science.gov (United States)

    Folger, Ori; Jerby, Livnat; Frezza, Christian; Gottlieb, Eyal; Ruppin, Eytan; Shlomi, Tomer

    2011-01-01

    The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled. PMID:21694718

  7. Target Selection for the SDSS-IV APOGEE-2 Survey

    Energy Technology Data Exchange (ETDEWEB)

    Zasowski, G. [Department of Physics and Astronomy, University of Utah, Salt Lake City, UT 84112 (United States); Cohen, R. E.; Carlberg, J. K.; Fleming, Scott W. [Space Telescope Science Institute, Baltimore, MD 21218 (United States); Chojnowski, S. D.; Holtzman, J. [Department of Astronomy, New Mexico State University, Las Cruces, NM 88001 (United States); Santana, F. [Departamento de Astronomía, Universidad de Chile, Santiago (Chile); Oelkers, R. J.; Bird, J. C. [Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37235 (United States); Andrews, B. [PITT PACC, Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Beaton, R. L. [The Observatories of the Carnegie Institution for Science, Pasadena, CA 91101 (United States); Bender, C.; Cunha, K. [Steward Observatory, The University of Arizona, Tucson, AZ 85719 (United States); Bovy, J. [Department of Astronomy and Astrophysics and Dunlap Institute for Astronomy and Astrophysics, University of Toronto, Toronto, ON M5S 3H4 (Canada); Covey, K. [Department of Physics and Astronomy, Western Washington University, Bellingham, WA 98225 (United States); Dell’Agli, F.; García-Hernández, D. A. [Departamento de Astrofísica, Universidad de La Laguna, and Instituto de Astrofísica de Canarias, La Laguna, Tenerife (Spain); Frinchaboy, P. M. [Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX 76129 (United States); Harding, P. [Department of Astronomy, Case Western Reserve University, Cleveland, OH 44106 (United States); Johnson, J. A., E-mail: gail.zasowski@gmail.com [Department of Astronomy, The Ohio State University, Columbus, OH 43210 (United States); and others

    2017-11-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ∼3 × 10{sup 5} stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  8. Target Selection for the SDSS-IV APOGEE-2 Survey

    Science.gov (United States)

    Zasowski, G.; Cohen, R. E.; Chojnowski, S. D.; Santana, F.; Oelkers, R. J.; Andrews, B.; Beaton, R. L.; Bender, C.; Bird, J. C.; Bovy, J.; Carlberg, J. K.; Covey, K.; Cunha, K.; Dell’Agli, F.; Fleming, Scott W.; Frinchaboy, P. M.; García-Hernández, D. A.; Harding, P.; Holtzman, J.; Johnson, J. A.; Kollmeier, J. A.; Majewski, S. R.; Mészáros, Sz.; Munn, J.; Muñoz, R. R.; Ness, M. K.; Nidever, D. L.; Poleski, R.; Román-Zúñiga, C.; Shetrone, M.; Simon, J. D.; Smith, V. V.; Sobeck, J. S.; Stringfellow, G. S.; Szigetiáros, L.; Tayar, J.; Troup, N.

    2017-11-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ∼3 × 105 stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  9. Local randomization in neighbor selection improves PRM roadmap quality

    KAUST Repository

    McMahon, Troy

    2012-10-01

    Probabilistic Roadmap Methods (PRMs) are one of the most used classes of motion planning methods. These sampling-based methods generate robot configurations (nodes) and then connect them to form a graph (roadmap) containing representative feasible pathways. A key step in PRM roadmap construction involves identifying a set of candidate neighbors for each node. Traditionally, these candidates are chosen to be the k-closest nodes based on a given distance metric. In this paper, we propose a new neighbor selection policy called LocalRand(k,K\\'), that first computes the K\\' closest nodes to a specified node and then selects k of those nodes at random. Intuitively, LocalRand attempts to benefit from random sampling while maintaining the higher levels of local planner success inherent to selecting more local neighbors. We provide a methodology for selecting the parameters k and K\\'. We perform an experimental comparison which shows that for both rigid and articulated robots, LocalRand results in roadmaps that are better connected than the traditional k-closest policy or a purely random neighbor selection policy. The cost required to achieve these results is shown to be comparable to k-closest. © 2012 IEEE.

  10. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  11. TSTMP: target selection for structural genomics of human transmembrane proteins.

    Science.gov (United States)

    Varga, Julia; Dobson, László; Reményi, István; Tusnády, Gábor E

    2017-01-04

    The TSTMP database is designed to help the target selection of human transmembrane proteins for structural genomics projects and structure modeling studies. Currently, there are only 60 known 3D structures among the polytopic human transmembrane proteins and about a further 600 could be modeled using existing structures. Although there are a great number of human transmembrane protein structures left to be determined, surprisingly only a small fraction of these proteins have 'selected' (or above) status according to the current version the TargetDB/TargetTrack database. This figure is even worse regarding those transmembrane proteins that would contribute the most to the structural coverage of the human transmembrane proteome. The database was built by sorting out proteins from the human transmembrane proteome with known structure and searching for suitable model structures for the remaining proteins by combining the results of a state-of-the-art transmembrane specific fold recognition algorithm and a sequence similarity search algorithm. Proteins were searched for homologues among the human transmembrane proteins in order to select targets whose successful structure determination would lead to the best structural coverage of the human transmembrane proteome. The pipeline constructed for creating the TSTMP database guarantees to keep the database up-to-date. The database is available at http://tstmp.enzim.ttk.mta.hu. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. Target Selection for the SDSS-III MARVELS Survey

    Science.gov (United States)

    Paegert, Martin; Stassun, Keivan G.; De Lee, Nathan; Pepper, Joshua; Fleming, Scott W.; Sivarani, Thirupathi; Mahadevan, Suvrath; Mack, Claude E., III; Dhital, Saurav; Hebb, Leslie; Ge, Jian

    2015-06-01

    We present the target selection process for the Multi-object APO Radial Velocity Exoplanets Large-area Survey (MARVELS), which is part of the Sloan Digital Sky Survey (SDSS) III. MARVELS is a medium-resolution (R ∼ 11,000) multi-fiber spectrograph capable of obtaining radial velocities for 60 objects at a time in order to find brown dwarfs and giant planets. The survey was configured to target dwarf stars with effective temperatures approximately between 4500 and 6250 K. For the first 2 years MARVELS relied on low-resolution spectroscopic pre-observations to estimate the effective temperature and log (g) for candidate stars and then selected suitable dwarf stars from this pool. Ultimately, the pre-observation spectra proved ineffective at filtering out giant stars; many giants were incorrectly classified as dwarfs, resulting in a giant contamination rate of ∼30% for the first phase of the MARVELS survey. Thereafter, the survey instead applied a reduced proper motion cut to eliminate giants and used the Infrared Flux Method to estimate effective temperatures, using only extant photmetric and proper-motion catalog information. The target selection method introduced here may be useful for other surveys that need to rely on extant catalog data for selection of specific stellar populations.

  13. Selecting a phoneme-to-grapheme mapping: Random or weighted selection?

    Directory of Open Access Journals (Sweden)

    Binna Lee

    2015-05-01

    Our findings demonstrate that random selection underestimates MOA’s PG correspondences whereas weighted selection predicts higher PG correspondences than he produces. To explain his intermediate spelling performance on PPEs, we will test additional approaches to weighing the relative probability of PG mappings, including using log frequencies, separating consonant and vowel status, and considering the number of grapheme options in each phoneme.

  14. Selection for altruism through random drift in variable size populations.

    Science.gov (United States)

    Houchmandzadeh, Bahram; Vallade, Marcel

    2012-05-10

    Altruistic behavior is defined as helping others at a cost to oneself and a lowered fitness. The lower fitness implies that altruists should be selected against, which is in contradiction with their widespread presence is nature. Present models of selection for altruism (kin or multilevel) show that altruistic behaviors can have 'hidden' advantages if the 'common good' produced by altruists is restricted to some related or unrelated groups. These models are mostly deterministic, or assume a frequency dependent fitness. Evolutionary dynamics is a competition between deterministic selection pressure and stochastic events due to random sampling from one generation to the next. We show here that an altruistic allele extending the carrying capacity of the habitat can win by increasing the random drift of "selfish" alleles. In other terms, the fixation probability of altruistic genes can be higher than those of a selfish ones, even though altruists have a smaller fitness. Moreover when populations are geographically structured, the altruists advantage can be highly amplified and the fixation probability of selfish genes can tend toward zero. The above results are obtained both by numerical and analytical calculations. Analytical results are obtained in the limit of large populations. The theory we present does not involve kin or multilevel selection, but is based on the existence of random drift in variable size populations. The model is a generalization of the original Fisher-Wright and Moran models where the carrying capacity depends on the number of altruists.

  15. Selection for altruism through random drift in variable size populations

    Directory of Open Access Journals (Sweden)

    Houchmandzadeh Bahram

    2012-05-01

    Full Text Available Abstract Background Altruistic behavior is defined as helping others at a cost to oneself and a lowered fitness. The lower fitness implies that altruists should be selected against, which is in contradiction with their widespread presence is nature. Present models of selection for altruism (kin or multilevel show that altruistic behaviors can have ‘hidden’ advantages if the ‘common good’ produced by altruists is restricted to some related or unrelated groups. These models are mostly deterministic, or assume a frequency dependent fitness. Results Evolutionary dynamics is a competition between deterministic selection pressure and stochastic events due to random sampling from one generation to the next. We show here that an altruistic allele extending the carrying capacity of the habitat can win by increasing the random drift of “selfish” alleles. In other terms, the fixation probability of altruistic genes can be higher than those of a selfish ones, even though altruists have a smaller fitness. Moreover when populations are geographically structured, the altruists advantage can be highly amplified and the fixation probability of selfish genes can tend toward zero. The above results are obtained both by numerical and analytical calculations. Analytical results are obtained in the limit of large populations. Conclusions The theory we present does not involve kin or multilevel selection, but is based on the existence of random drift in variable size populations. The model is a generalization of the original Fisher-Wright and Moran models where the carrying capacity depends on the number of altruists.

  16. Selection and trajectory design to mission secondary targets

    Science.gov (United States)

    Victorino Sarli, Bruno; Kawakatsu, Yasuhiro

    2017-02-01

    Recently, with new trajectory design techniques and use of low-thrust propulsion systems, missions have become more efficient and cheaper with respect to propellant. As a way to increase the mission's value and scientific return, secondary targets close to the main trajectory are often added with a small change in the transfer trajectory. As a result of their large number, importance and facility to perform a flyby, asteroids are commonly used as such targets. This work uses the Primer Vector theory to define the direction and magnitude of the thrust for a minimum fuel consumption problem. The design of a low-thrust trajectory with a midcourse asteroid flyby is not only challenging for the low-thrust problem solution, but also with respect to the selection of a target and its flyby point. Currently more than 700,000 minor bodies have been identified, which generates a very large number of possible flyby points. This work uses a combination of reachability, reference orbit, and linear theory to select appropriate candidates, drastically reducing the simulation time, to be later included in the main trajectory and optimized. Two test cases are presented using the aforementioned selection process and optimization to add and design a secondary flyby to a mission with the primary objective of 3200 Phaethon flyby and 25143 Itokawa rendezvous.

  17. TARGET SELECTION FOR THE LBTI EXOZODI KEY SCIENCE PROGRAM

    Energy Technology Data Exchange (ETDEWEB)

    Weinberger, Alycia J. [Department of Terrestrial Magnetism, Carnegie Institution for Science, 5241 Broad Branch Road NW, Washington, DC 20015 (United States); Bryden, Geoff; Mennesson, Bertrand; Serabyn, Eugene [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Dr, Pasadena, CA 91109 (United States); Kennedy, Grant M.; Wyatt, Mark C. [Institute of Astronomy, University of Cambridge, Madingley Road, Cambridge CB3 0HA (United Kingdom); Roberge, Aki; Danchi, William C.; Stapelfeldt, Karl R. [Exoplanets and Stellar Astrophysics Laboratory, NASA Goddard Space Flight Center, Code 667, Greenbelt, MD 20771 (United States); Defrère, Denis; Hinz, Philip M.; Rieke, George; Bailey, Vanessa P.; Skemer, Andrew J. [Steward Observatory, University of Arizona, 933 North Cherry Lane, Tucson, AZ 85721 (United States); Millan-Gabet, Rafael [NASA Exoplanet Science Institute, California Institute of Technology, Pasadena, CA 91125 (United States); Haniff, Chris, E-mail: weinberger@dtm.ciw.edu [Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE (United Kingdom)

    2015-02-01

    The Hunt for Observable Signatures of Terrestrial planetary Systems (HOSTS) on the Large Binocular Telescope Interferometer will survey nearby stars for faint emission arising from ∼300 K dust (exozodiacal dust), and aims to determine the exozodiacal dust luminosity function. HOSTS results will enable planning for future space telescopes aimed at direct spectroscopy of habitable zone terrestrial planets, as well as greater understanding of the evolution of exozodiacal disks and planetary systems. We lay out here the considerations that lead to the final HOSTS target list. Our target selection strategy maximizes the ability of the survey to constrain the exozodi luminosity function by selecting a combination of stars selected for suitability as targets of future missions and as sensitive exozodi probes. With a survey of approximately 50 stars, we show that HOSTS can enable an understanding of the statistical distribution of warm dust around various types of stars and is robust to the effects of varying levels of survey sensitivity induced by weather conditions.

  18. Dynamic interactions between visual working memory and saccade target selection

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P.; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-01-01

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. PMID:25228628

  19. Dynamic interactions between visual working memory and saccade target selection.

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-09-16

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. © 2014 ARVO.

  20. Target inhibition networks: predicting selective combinations of druggable targets to block cancer survival pathways.

    Directory of Open Access Journals (Sweden)

    Jing Tang

    Full Text Available A recent trend in drug development is to identify drug combinations or multi-target agents that effectively modify multiple nodes of disease-associated networks. Such polypharmacological effects may reduce the risk of emerging drug resistance by means of attacking the disease networks through synergistic and synthetic lethal interactions. However, due to the exponentially increasing number of potential drug and target combinations, systematic approaches are needed for prioritizing the most potent multi-target alternatives on a global network level. We took a functional systems pharmacology approach toward the identification of selective target combinations for specific cancer cells by combining large-scale screening data on drug treatment efficacies and drug-target binding affinities. Our model-based prediction approach, named TIMMA, takes advantage of the polypharmacological effects of drugs and infers combinatorial drug efficacies through system-level target inhibition networks. Case studies in MCF-7 and MDA-MB-231 breast cancer and BxPC-3 pancreatic cancer cells demonstrated how the target inhibition modeling allows systematic exploration of functional interactions between drugs and their targets to maximally inhibit multiple survival pathways in a given cancer type. The TIMMA prediction results were experimentally validated by means of systematic siRNA-mediated silencing of the selected targets and their pairwise combinations, showing increased ability to identify not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of non-additive drug efficacies. These system-level analyses were enabled by a novel model construction method utilizing maximization and minimization rules, as well as a model selection algorithm based on sequential forward floating search. Compared with an existing computational solution, TIMMA showed both enhanced

  1. Simulated Performance Evaluation of a Selective Tracker Through Random Scenario Generation

    DEFF Research Database (Denmark)

    Hussain, Dil Muhammad Akbar

    2006-01-01

      The paper presents a simulation study on the performance of a target tracker using selective track splitting filter algorithm through a random scenario implemented on a digital signal processor.  In a typical track splitting filter all the observation which fall inside a likelihood ellipse...... are used for update, however, in our proposed selective track splitting filter less number of observations are used for track update.  Much of the previous performance work [1] has been done on specific (deterministic) scenarios. One of the reasons for considering the specific scenarios, which were...

  2. Engineering novel cell surface chemistry for selective tumor cell targeting

    Energy Technology Data Exchange (ETDEWEB)

    Bertozzi, C.R. [Univ. of California, Berkeley, CA (United States)]|[Lawrence Berkeley National Lab., CA (United States)

    1997-12-31

    A common feature of many different cancers is the high expression level of the two monosaccharides sialic acid and fucose within the context of cell-surface associated glycoconjugates. A correlation has been made between hypersialylation and/or hyperfucosylation and the highly metastatic phenotype. Thus, a targeting strategy based on sialic acid or fucose expression would be a powerful tool for the development of new cancer cell-selective therapies and diagnostic agents. We have discovered that ketone groups can be incorporated metabolically into cell-surface associated sialic acids. The ketone is can be covalently ligated with hydrazide functionalized proteins or small molecules under physiological conditions. Thus, we have discovered a mechanism to selectively target hydrazide conjugates to highly sialylated cells such as cancer cells. Applications of this technology to the generation of novel cancer cell-selective toxins and MRI contrast reagents will be discussed, in addition to progress towards the use of cell surface fucose residues as vehicles for ketone expression.

  3. Selective inhibition of retinal angiogenesis by targeting PI3 kinase.

    Directory of Open Access Journals (Sweden)

    Yolanda Alvarez

    Full Text Available Ocular neovascularisation is a pathological hallmark of some forms of debilitating blindness including diabetic retinopathy, age related macular degeneration and retinopathy of prematurity. Current therapies for delaying unwanted ocular angiogenesis include laser surgery or molecular inhibition of the pro-angiogenic factor VEGF. However, targeting of angiogenic pathways other than, or in combination to VEGF, may lead to more effective and safer inhibitors of intraocular angiogenesis. In a small chemical screen using zebrafish, we identify LY294002 as an effective and selective inhibitor of both developmental and ectopic hyaloid angiogenesis in the eye. LY294002, a PI3 kinase inhibitor, exerts its anti-angiogenic effect in a dose-dependent manner, without perturbing existing vessels. Significantly, LY294002 delivered by intraocular injection, significantly inhibits ocular angiogenesis without systemic side-effects and without diminishing visual function. Thus, targeting of PI3 kinase pathways has the potential to effectively and safely treat neovascularisation in eye disease.

  4. An assessment of spacecraft target mode selection methods

    Science.gov (United States)

    Mercer, J. F.; Aglietti, G. S.; Remedia, M.; Kiley, A.

    2017-11-01

    Coupled Loads Analyses (CLAs), using finite element models (FEMs) of the spacecraft and launch vehicle to simulate critical flight events, are performed in order to determine the dynamic loadings that will be experienced by spacecraft during launch. A validation process is carried out on the spacecraft FEM beforehand to ensure that the dynamics of the analytical model sufficiently represent the behavior of the physical hardware. One aspect of concern is the containment of the FEM correlation and update effort to focus on the vibration modes which are most likely to be excited under test and CLA conditions. This study therefore provides new insight into the prioritization of spacecraft FEM modes for correlation to base-shake vibration test data. The work involved example application to large, unique, scientific spacecraft, with modern FEMs comprising over a million degrees of freedom. This comprehensive investigation explores: the modes inherently important to the spacecraft structures, irrespective of excitation; the particular 'critical modes' which produce peak responses to CLA level excitation; an assessment of several traditional target mode selection methods in terms of ability to predict these 'critical modes'; and an indication of the level of correlation these FEM modes achieve compared to corresponding test data. Findings indicate that, although the traditional methods of target mode selection have merit and are able to identify many of the modes of significance to the spacecraft, there are 'critical modes' which may be missed by conventional application of these methods. The use of different thresholds to select potential target modes from these parameters would enable identification of many of these missed modes. Ultimately, some consideration of the expected excitations is required to predict all modes likely to contribute to the response of the spacecraft in operation.

  5. Interference-aware random beam selection for spectrum sharing systems

    KAUST Repository

    Abdallah, Mohamed M.

    2012-09-01

    Spectrum sharing systems have been introduced to alleviate the problem of spectrum scarcity by allowing secondary unlicensed networks to share the spectrum with primary licensed networks under acceptable interference levels to the primary users. In this paper, we develop interference-aware random beam selection schemes that provide enhanced throughput for the secondary link under the condition that the interference observed at the primary link is within a predetermined acceptable value. For a secondary transmitter equipped with multiple antennas, our schemes select a random beam, among a set of power- optimized orthogonal random beams, that maximizes the capacity of the secondary link while satisfying the interference constraint at the primary receiver for different levels of feedback information describing the interference level at the primary receiver. For the proposed schemes, we develop a statistical analysis for the signal-to-noise and interference ratio (SINR) statistics as well as the capacity of the secondary link. Finally, we present numerical results that study the effect of system parameters including number of beams and the maximum transmission power on the capacity of the secondary link attained using the proposed schemes. © 2012 IEEE.

  6. Targets of balancing selection in the human genome

    DEFF Research Database (Denmark)

    Andrés, Aida M; Hubisz, Melissa J; Indap, Amit

    2009-01-01

    Balancing selection is potentially an important biological force for maintaining advantageous genetic diversity in populations, including variation that is responsible for long-term adaptation to the environment. By serving as a means to maintain genetic variation, it may be particularly relevant...... to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set......, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment...

  7. Oncotripsy: Targeting cancer cells selectively via resonant harmonic excitation

    CERN Document Server

    Heyden, Stefanie

    2015-01-01

    We investigate a method of selectively targeting cancer cells by means of ultrasound harmonic excitation at their resonance frequency, which we refer to as oncotripsy. The geometric model of the cells takes into account the cytoplasm, nucleus and nucleolus, as well as the plasma membrane and nuclear envelope. Material properties are varied within a pathophysiologically-relevant range. A first modal analysis reveals the existence of a spectral gap between the natural frequencies and, most importantly, resonant growth rates of healthy and cancerous cells. The results of the modal analysis are verified by simulating the fully-nonlinear transient response of healthy and cancerous cells at resonance. The fully nonlinear analysis confirms that cancerous cells can be selectively taken to lysis by the application of carefully tuned ultrasound harmonic excitation while simultaneously leaving healthy cells intact.

  8. Selective Targeting to Glioma with Nucleic Acid Aptamers.

    Directory of Open Access Journals (Sweden)

    Shraddha Aptekar

    Full Text Available Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 ± 4.60 nM and Kd, 21.11 ± 3.30 nM respectively to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma.

  9. Moving Target Techniques: Cyber Resilience throught Randomization, Diversity, and Dynamism

    Science.gov (United States)

    2017-03-03

    cyber resilience that attempts to rebalance the cyber landscape is known as cyber moving target (MT) (or just moving target) techniques. Moving target...articulated threat model , it may be unclear to network defenders what threat needs to be mitigated and thus how best to deploy the defensive...systems and hardware architectures . For example, the application can run on top of a platform consisting of the Fedora operating system and x86

  10. Relativistic effects on galaxy redshift samples due to target selection

    Science.gov (United States)

    Alam, Shadab; Croft, Rupert A. C.; Ho, Shirley; Zhu, Hongyu; Giusarma, Elena

    2017-10-01

    In a galaxy redshift survey, the objects to be targeted for spectra are selected from a photometrically observed sample. The observed magnitudes and colours of galaxies in this parent sample will be affected by their peculiar velocities, through relativistic Doppler and relativistic beaming effects. In this paper, we compute the resulting expected changes in galaxy photometry. The magnitudes of the relativistic effects are a function of redshift, stellar mass, galaxy velocity and velocity direction. We focus on the CMASS sample from the Sloan Digital Sky Survey (SDSS) and Baryon Oscillation Spectroscopic Survey (BOSS), which is selected on the basis of colour and magnitude. We find that 0.10 per cent of the sample (∼585 galaxies) has been scattered into the targeted region of colour-magnitude space by relativistic effects, and conversely 0.09 per cent of the sample (∼532 galaxies) has been scattered out. Observational consequences of these effects include an asymmetry in clustering statistics, which we explore in a companion paper. Here, we compute a set of weights that can be used to remove the effect of modulations introduced into the density field inferred from a galaxy sample. We conclude by investigating the possible effects of these relativistic modulation on large-scale clustering of the galaxy sample.

  11. Positive-negative-selection-mediated gene targeting in rice

    Directory of Open Access Journals (Sweden)

    Zenpei eShimatani

    2015-01-01

    Full Text Available Gene targeting (GT refers to the designed modification of genomic sequence(s through homologous recombination (HR. GT is a powerful tool both for the study of gene function and for molecular breeding. However, in transformation of higher plants, non-homologous end joining (NHEJ occurs overwhelmingly in somatic cells, masking HR-mediated GT. Positive-negative selection (PNS is an approach for finding HR-mediated GT events because it can eliminate NHEJ effectively by expression of a negative-selection marker gene. In rice—a major crop worldwide—reproducible PNS-mediated GT of endogenous genes has now been successfully achieved. The procedure is based on strong PNS using diphtheria toxin A-fragment as a negative marker, and has succeeded in the directed modification of several endogenous rice genes in various ways. In addition to gene knock-outs and knock-ins, a nucleotide substitution in a target gene was also achieved recently. This review presents a summary of the development of the rice PNS system, highlighting its advantages. Different types of gene modification and gene editing aimed at developing new plant breeding technology (NPBT based on PNS are discussed.

  12. Landslide susceptibility mapping in three selected target zones in Afghanistan

    Science.gov (United States)

    Schwanghart, Wolfgang; Seegers, Joe; Zeilinger, Gerold

    2015-04-01

    In May 2014, a large and mobile landslide destroyed the village Ab Barek, a village in Badakshan Province, Afghanistan. The landslide caused several hundred fatalities and once again demonstrated the vulnerability of Afghanistan's population to extreme natural events following more than 30 years of civil war and violent conflict. Increasing the capacity of Afghanistan's population by strengthening the disaster preparedness and management of responsible government authorities and institutions is thus a major component of international cooperation and development strategies. Afghanistan is characterized by high relief and widely varying rock types that largely determine the spatial distribution as well as emplacement modes of mass movements. The major aim of our study is to characterize this variability by conducting a landslide susceptibility analysis in three selected target zones: Greater Kabul Area, Badakhshan Province and Takhar Province. We expand on an existing landslide database by mapping landforms diagnostic for landslides (e.g. head scarps, normal faults and tension cracks), and historical landslide scars and landslide deposits by visual interpretation of high-resolution satellite imagery. We conduct magnitude frequency analysis within subregional physiogeographic classes based on geological maps, climatological and topographic data to identify regional parameters influencing landslide magnitude and frequency. In addition, we prepare a landslide susceptibility map for each area using the Weight-of-Evidence model. Preliminary results show that the three selected target zones vastly differ in modes of landsliding. Low magnitude but frequent rockfall events are a major hazard in the Greater Kabul Area threatening buildings and infrastructure encroaching steep terrain in the city's outskirts. Mass movements in loess covered areas of Badakshan are characterized by medium to large magnitudes. This spatial variability of characteristic landslide magnitudes and

  13. Triatoma dimidiata infestation in Chagas disease endemic regions of Guatemala: comparison of random and targeted cross-sectional surveys.

    Directory of Open Access Journals (Sweden)

    Raymond J King

    approximately 0.64 in the targeted surveys in both regions. Sensitivity did not differ between surveys, but the positive predictive value was significantly greater in the random surveys. CONCLUSIONS/SIGNIFICANCE: Surprisingly, targeted surveys were not more effective at determining T. dimidiata prevalence or at directing control to high risk villages in comparison to random surveys. We recommend that random surveys should be selected over targeted surveys whenever possible, particularly when the focus is on directing disease control and elimination and when risk factor association has not been evaluated for all regions under investigation.

  14. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2012-01-01

    Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

  15. Unbiased split variable selection for random survival forests using maximally selected rank statistics.

    Science.gov (United States)

    Wright, Marvin N; Dankowski, Theresa; Ziegler, Andreas

    2017-04-15

    The most popular approach for analyzing survival data is the Cox regression model. The Cox model may, however, be misspecified, and its proportionality assumption may not always be fulfilled. An alternative approach for survival prediction is random forests for survival outcomes. The standard split criterion for random survival forests is the log-rank test statistic, which favors splitting variables with many possible split points. Conditional inference forests avoid this split variable selection bias. However, linear rank statistics are utilized by default in conditional inference forests to select the optimal splitting variable, which cannot detect non-linear effects in the independent variables. An alternative is to use maximally selected rank statistics for the split point selection. As in conditional inference forests, splitting variables are compared on the p-value scale. However, instead of the conditional Monte-Carlo approach used in conditional inference forests, p-value approximations are employed. We describe several p-value approximations and the implementation of the proposed random forest approach. A simulation study demonstrates that unbiased split variable selection is possible. However, there is a trade-off between unbiased split variable selection and runtime. In benchmark studies of prediction performance on simulated and real datasets, the new method performs better than random survival forests if informative dichotomous variables are combined with uninformative variables with more categories and better than conditional inference forests if non-linear covariate effects are included. In a runtime comparison, the method proves to be computationally faster than both alternatives, if a simple p-value approximation is used. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  16. The signature of positive selection at randomly chosen loci.

    Science.gov (United States)

    Przeworski, Molly

    2002-03-01

    In Drosophila and humans, there are accumulating examples of loci with a significant excess of high-frequency-derived alleles or high levels of linkage disequilibrium, relative to a neutral model of a random-mating population of constant size. These are features expected after a recent selective sweep. Their prevalence suggests that positive directional selection may be widespread in both species. However, as I show here, these features do not persist long after the sweep ends: The high-frequency alleles drift to fixation and no longer contribute to polymorphism, while linkage disequilibrium is broken down by recombination. As a result, loci chosen without independent evidence of recent selection are not expected to exhibit either of these features, even if they have been affected by numerous sweeps in their genealogical history. How then can we explain the patterns in the data? One possibility is population structure, with unequal sampling from different subpopulations. Alternatively, positive selection may not operate as is commonly modeled. In particular, the rate of fixation of advantageous mutations may have increased in the recent past.

  17. Randomized controlled trial of internal and external targeted temperature management methods in post- cardiac arrest patients.

    Science.gov (United States)

    Look, Xinqi; Li, Huihua; Ng, Mingwei; Lim, Eric Tien Siang; Pothiawala, Sohil; Tan, Kenneth Boon Kiat; Sewa, Duu Wen; Shahidah, Nur; Pek, Pin Pin; Ong, Marcus Eng Hock

    2017-07-05

    Targeted temperature management post-cardiac arrest is currently implemented using various methods, broadly categorized as internal and external. This study aimed to evaluate survival-to-hospital discharge and neurological outcomes (Glasgow-Pittsburgh Score) of post-cardiac arrest patients undergoing internal cooling verses external cooling. A randomized controlled trial of post-resuscitation cardiac arrest patients was conducted from October 2008-September 2014. Patients were randomized to either internal or external cooling methods. Historical controls were selected matched by age and gender. Analysis using SPSS version 21.0 presented descriptive statistics and frequencies while univariate logistic regression was done using R 3.1.3. 23 patients were randomized to internal cooling and 22 patients to external cooling and 42 matched controls were selected. No significant difference was seen between internal and external cooling in terms of survival, neurological outcomes and complications. However in the internal cooling arm, there was lower risk of developing overcooling (p=0.01) and rebound hyperthermia (p=0.02). Compared to normothermia, internal cooling had higher survival (OR=3.36, 95% CI=(1.130, 10.412), and lower risk of developing cardiac arrhythmias (OR=0.18, 95% CI=(0.04, 0.63)). Subgroup analysis showed those with cardiac cause of arrest (OR=4.29, 95% CI=(1.26, 15.80)) and sustained ROSC (OR=5.50, 95% CI=(1.64, 20.39)) had better survival with internal cooling compared to normothermia. Cooling curves showed tighter temperature control for internal compared to external cooling. Internal cooling showed tighter temperature control compared to external cooling. Internal cooling can potentially provide better survival-to-hospital discharge outcomes and reduce cardiac arrhythmia complications in carefully selected patients as compared to normothermia. Copyright © 2017. Published by Elsevier Inc.

  18. Random Noise Monopulse Radar System for Covert Tracking of Targets

    Science.gov (United States)

    Narayanan, Ram M.

    2002-07-01

    The University of Nebraska is currently developing a unique monopulse radar concept based on the use of random noise signal for covert tracking applications. This project is funded by the Missile Defense Agency (MDA). The advantage of this system over conventional frequency-modulated continuous wave (FMCW) or short pulse systems is its covertness resulting from the random waveform's immunity from interception and jamming. The system integrates a novel heterodyne correlation receiver with conventional monopulse architecture. Based on the previous work such as random noise interferometry, a series of theoretical analysis and simulations were conducted to examine the potential performance of this monopulse system. Furthermore, a prototype system is under development to exploit practical design aspects of phase comparison angle measurement. It is revealed that random noise monopulse radar can provide the same function as traditional monopulse radar, i.e., implement range and angular estimation and tracking in real time. The bandwidth of random noise signal can be optimized to achieve the best range resolution as well as the angular accuracy.

  19. Utilization of OIM for Measurement Selection in Multistatic Target Tracking

    Directory of Open Access Journals (Sweden)

    G. Soysal

    2014-04-01

    Full Text Available The sensor management problem can be expressed as obtaining the state estimation with desired accuracy by utilizing the resources effectively. In the literature, there are two principal approaches to this problem, namely task-driven and information driven sensor management. Performance metrics for both task-driven and information driven sensor management frameworks suffer from the heavy computational burden due to the evaluation of expectations or are available only in simulation. In this paper, the Observed Information Matrix (OIM, which is widely used in statistical practice as a surrogate for the Fisher Information Matrix (FIM in difficult problems, has been proposed as a metric that can be used in sensor management. Recursive computation of OIM has been derived for the cases with linear and nonlinear system dynamics corrupted with additive Gaussian noise. The usefulness of OIM in sensor selection in multistatic target tracking has been demonstrated via simulations.

  20. Random Scenario Generation for a Multiple Target Tracking Environment Evaluation

    DEFF Research Database (Denmark)

    Hussain, Dil Muhammad Akbar

    2006-01-01

    The paper presents a simulation study on the generation of a random scenario for the performance of track splitting algorithm on a digital signal processor.  Much of the previous work [1] was done on specific (deterministic) scenarios. One of the reasons for considering the specific scenarios, wh...

  1. CD133, Selectively Targeting the Root of Cancer

    Directory of Open Access Journals (Sweden)

    Jörg U. Schmohl

    2016-05-01

    Full Text Available Cancer stem cells (CSC are capable of promoting tumor initiation and self-renewal, two important hallmarks of carcinoma formation. This population comprises a small percentage of the tumor mass and is highly resistant to chemotherapy, causing the most difficult problem in the field of cancer research, drug refractory relapse. Many CSC markers have been reported. One of the most promising and perhaps least ubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequently expressed on CSC. There is evidence that directly targeting CD133 with biological drugs might be the most effective way to eliminate CSC. We have investigated two entirely unrelated, but highly effective approaches for selectively targeting CD133. The first involves using a special anti-CD133 single chain variable fragment (scFv to deliver a catalytic toxin. The second utilizes this same scFv to deliver components of the immune system. In this review, we discuss the development and current status of these CD133 associated biological agents. Together, they show exceptional promise by specific and efficient CSC elimination.

  2. Blind Measurement Selection: A Random Matrix Theory Approach

    KAUST Repository

    Elkhalil, Khalil

    2016-12-14

    This paper considers the problem of selecting a set of $k$ measurements from $n$ available sensor observations. The selected measurements should minimize a certain error function assessing the error in estimating a certain $m$ dimensional parameter vector. The exhaustive search inspecting each of the $n\\\\choose k$ possible choices would require a very high computational complexity and as such is not practical for large $n$ and $k$. Alternative methods with low complexity have recently been investigated but their main drawbacks are that 1) they require perfect knowledge of the measurement matrix and 2) they need to be applied at the pace of change of the measurement matrix. To overcome these issues, we consider the asymptotic regime in which $k$, $n$ and $m$ grow large at the same pace. Tools from random matrix theory are then used to approximate in closed-form the most important error measures that are commonly used. The asymptotic approximations are then leveraged to select properly $k$ measurements exhibiting low values for the asymptotic error measures. Two heuristic algorithms are proposed: the first one merely consists in applying the convex optimization artifice to the asymptotic error measure. The second algorithm is a low-complexity greedy algorithm that attempts to look for a sufficiently good solution for the original minimization problem. The greedy algorithm can be applied to both the exact and the asymptotic error measures and can be thus implemented in blind and channel-aware fashions. We present two potential applications where the proposed algorithms can be used, namely antenna selection for uplink transmissions in large scale multi-user systems and sensor selection for wireless sensor networks. Numerical results are also presented and sustain the efficiency of the proposed blind methods in reaching the performances of channel-aware algorithms.

  3. Pediatric selective mutism therapy: a randomized controlled trial.

    Science.gov (United States)

    Esposito, Maria; Gimigliano, Francesca; Barillari, Maria R; Precenzano, Francesco; Ruberto, Maria; Sepe, Joseph; Barillari, Umberto; Gimigliano, Raffaele; Militerni, Roberto; Messina, Giovanni; Carotenuto, Marco

    2017-10-01

    Selective mutism (SM) is a rare disease in children coded by DSM-5 as an anxiety disorder. Despite the disabling nature of the disease, there is still no specific treatment. The aims of this study were to verify the efficacy of six-month standard psychomotor treatment and the positive changes in lifestyle, in a population of children affected by SM. Randomized controlled trial registered in the European Clinical Trials Registry (EuDract 2015-001161-36). University third level Centre (Child and Adolescent Neuropsychiatry Clinic). Study population was composed by 67 children in group A (psychomotricity treatment) (35 M, mean age 7.84±1.15) and 71 children in group B (behavioral and educational counseling) (37 M, mean age 7.75±1.36). Psychomotor treatment was administered by trained child therapists in residential settings three times per week. Each child was treated for the whole period by the same therapist and all the therapists shared the same protocol. The standard psychomotor session length is of 45 minutes. At T0 and after 6 months (T1) of treatments, patients underwent a behavioral and SM severity assessment. To verify the effects of the psychomotor management, the Child Behavior Checklist questionnaire (CBCL) and Selective Mutism Questionnaire (SMQ) were administered to the parents. After 6 months of psychomotor treatment SM children showed a significant reduction among CBCL scores such as in social relations, anxious/depressed, social problems and total problems (Ppsychomotricity a safe and efficacy therapy for pediatric selective mutism.

  4. Optimizing Event Selection with the Random Grid Search

    Energy Technology Data Exchange (ETDEWEB)

    Bhat, Pushpalatha C. [Fermilab; Prosper, Harrison B. [Florida State U.; Sekmen, Sezen [Kyungpook Natl. U.; Stewart, Chip [Broad Inst., Cambridge

    2017-06-29

    The random grid search (RGS) is a simple, but efficient, stochastic algorithm to find optimal cuts that was developed in the context of the search for the top quark at Fermilab in the mid-1990s. The algorithm, and associated code, have been enhanced recently with the introduction of two new cut types, one of which has been successfully used in searches for supersymmetry at the Large Hadron Collider. The RGS optimization algorithm is described along with the recent developments, which are illustrated with two examples from particle physics. One explores the optimization of the selection of vector boson fusion events in the four-lepton decay mode of the Higgs boson and the other optimizes SUSY searches using boosted objects and the razor variables.

  5. Selecting targets from eukaryotic parasites for structural genomics and drug discovery.

    Science.gov (United States)

    Phan, Isabelle Q H; Stacy, Robin; Myler, Peter J

    2014-01-01

    The selection of targets is the first step for any structural genomics project. The application of structural genomics approaches to drug discovery also starts with the selection of targets. Here, three protocols are described that were developed to select targets from eukaryotic pathogens. These protocols could also be applied to other drug discovery projects.

  6. Selecting targets from eukaryotic parasites for structural genomics and drug discovery

    Science.gov (United States)

    Phan, Isabelle Q. H.; Stacy, Robin; Myler, Peter J.

    2015-01-01

    The selection of targets is the first step for any structural genomics project. The application of structural genomics approaches to drug discovery also starts with the selection of targets. Here, three protocols are described that were developed to select targets from eukaryotic pathogens. These protocols could also be applied to other drug discovery projects. PMID:24590708

  7. Rapid selection of accessible and cleavable sites in RNA by Escherichia coli RNase P and random external guide sequences

    OpenAIRE

    Lundblad, Eirik W.; Xiao, Gaoping; Ko, Jae-hyeong; Altman, Sidney

    2008-01-01

    A method of inhibiting the expression of particular genes by using external guide sequences (EGSs) has been improved in its rapidity and specificity. Random EGSs that have 14-nt random sequences are used in the selection procedure for an EGS that attacks the mRNA for a gene in a particular location. A mixture of the random EGSs, the particular target RNA, and RNase P is used in the diagnostic procedure, which, after completion, is analyzed in a gel with suitable control lanes. Within a few ho...

  8. A data mining approach to selecting herbs with similar efficacy: Targeted selection methods based on medical subject headings (MeSH).

    Science.gov (United States)

    Yea, Sang-Jun; Seong, BoSeok; Jang, Yunji; Kim, Chul

    2016-04-22

    Natural products have long been the most important source of ingredients in the discovery of new drugs. Moreover, since the Nagoya Protocol, finding alternative herbs with similar efficacy in traditional medicine has become a very important issue. Although random selection is a common method of finding ethno-medicinal herbs of similar efficacy, it proved to be less effective; therefore, this paper proposes a novel targeted selection method using data mining approaches in the MEDLINE database in order to identify and select herbs with a similar degree of efficacy. From among sixteen categories of medical subject headings (MeSH) descriptors, three categories containing terms related to herbal compounds, efficacy, toxicity, and the metabolic process were selected. In order to select herbs of similar efficacy in a targeted way, we adopted the similarity measurement method based on MeSH. In order to evaluate the proposed algorithm, we built up three different validation datasets which contain lists of original herbs and corresponding medicinal herbs of similar efficacy. The average area under curve (AUC) of the proposed algorithm was found to be about 500% larger than the random selection method. We found that the proposed algorithm puts more hits at the front of the top-10 list than the random selection method, and precisely discerns the efficacy of the herbs. It was also found that the AUC of the experiments either remained the same or increased slightly in all three validation datasets as the search range was increased. This study reveals and proves that the proposed algorithm is significantly more accurate and efficient in finding alternative herbs of similar efficacy than the random selection method. As such, it is hoped that this approach will be used in diverse applications in the ethno-pharmacology field. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  9. Selected attributes of polyphenols in targeting oxidative stress in cancer.

    Science.gov (United States)

    Stepanic, Visnja; Gasparovic, Ana Cipak; Troselj, Koraljka Gall; Amic, Dragan; Zarkovic, Neven

    2015-01-01

    Various plant polyphenols have been recognized as redox active molecules. This review discusses some aspects of polyphenols' modes of redox action, corresponding structure-activity relationships and their potential to be applied as adjuvants to conventional cytostatic drugs. Polyphenols' antioxidative capacity has been discussed as the basis for targeting oxidative stress and, consequently, for their chemopreventive and anti-inflammatory activities, which may alleviate side-effects on normal cells arising from oxidative stress caused by cytostatics. Some polyphenols may scavenge various free radicals directly, and some of them are found to suppress free radical production through inhibiting NADPH oxidases and xanthine oxidase. Additionally, polyphenols may increase antioxidative defense in normal cells by increasing the activity of NRF2, transcription factor for many protective proteins. The activation of the NRF2-mediated signaling pathways in cancer cells results in chemoresistance. Luteolin, apigenin and chrysin reduce NRF2 expression and increase the chemosensitivity of cancer cells to cytostatic drugs. Their common 5,7-dihydroxy-4H-chromen-4-one moiety, may represent a starting pharmacophore model for designing novel, non-toxic compounds for overcoming chemoresistance. However, prooxidative activity of some polyphenols (quercetin, EGCG) may also provide a basis for their use as chemotherapeutic adjuvants since they may enhance cytotoxic effects of cytostatics selectively on cancer cells. However, considerable caution is needed in applying polyphenols to anticancer therapy, since their effects greatly depend on the applied dose, the cell type, exposure time and environmental conditions.

  10. Saccade-target selection of dyslexic children when reading Chinese.

    Science.gov (United States)

    Pan, Jinger; Yan, Ming; Laubrock, Jochen; Shu, Hua; Kliegl, Reinhold

    2014-04-01

    This study investigates the eye movements of dyslexic children and their age-matched controls when reading Chinese. Dyslexic children exhibited more and longer fixations than age-matched control children, and an increase of word length resulted in a greater increase in the number of fixations and gaze durations for the dyslexic than for the control readers. The report focuses on the finding that there was a significant difference between the two groups in the fixation landing position as a function of word length in single-fixation cases, while there was no such difference in the initial fixation of multi-fixation cases. We also found that both groups had longer incoming saccade amplitudes while the launch sites were closer to the word in single fixation cases than in multi-fixation cases. Our results suggest that dyslexic children's inefficient lexical processing, in combination with the absence of orthographic word boundaries in Chinese, leads them to select saccade targets at the beginning of words conservatively. These findings provide further evidence for parafoveal word segmentation during reading of Chinese sentences. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Selective adaptation of internally triggered saccades made to visual targets

    OpenAIRE

    Erkelens, C.J.; Hulleman, J

    1993-01-01

    We examined whether internally triggered saccades made to a nonjumping target (I-saccades) could be adapted independently from externally triggered saccades induced by a jumping target (E-saccades). Five subjects made I-saccades between two fixed targets, one placed straight ahead and the other one positioned at an eccentricity of 17.5°. The peripheral target was displaced to an eccentricity of 8.75° during the saccadic movements toward this target. Amplitudes of the I-saccades made from the ...

  12. Target product selection - where can Molecular Pharming make the difference?

    Science.gov (United States)

    Paul, Mathew J; Teh, Audrey Y H; Twyman, Richard M; Ma, Julian K-C

    2013-01-01

    Four major developments have taken place in the world of Molecular Pharming recently. In the USA, the DARPA initiative challenged plant biotechnology companies to develop strategies for the large-scale manufacture of influenza vaccines, resulting in a successful Phase I clinical trial; in Europe the Pharma-Planta academic consortium gained regulatory approval for a plant-derived monoclonal antibody and completed a first-in-human phase I clinical trial; the Dutch pharmaceutical company Synthon acquired the assets of Biolex Therapeutics, an established Molecular Pharming company with several clinical candidates produced in their proprietary LEX system based on aquatic plants; and finally, the Israeli biotechnology company Protalix Biotherapeutics won FDA approval for the commercial release of a recombinant form of the enzyme glucocerebrosidase produced in carrot cells, the first plant biotechnology-derived biopharmaceutical in the world approved for the market. Commercial momentum is gathering pace with additional candidates now undergoing or awaiting approval for phase III clinical trials. Filling the product pipeline is vital to establish commercial sustainability, and the selection of appropriate target products for Molecular Pharming will be a critical factor. An interesting feature of the four stories outlined above is that they span the use of very different platform technologies addressing different types of molecules which aim to satisfy distinct market demands. In each case, Molecular Pharming was an economically and technically suitable approach, but this decisionmaking process is not necessarily straightforward. Although the various technologies available to Molecular Pharming are broad ranging and flexible, competing technologies are better established, so there needs to be a compelling reason to move into plants. It is most unlikely that plant biotechnology will be the answer for the whole biologics field. In this article, we discuss the current plant

  13. Targeting Functional Decline in Alzheimer Disease: A Randomized Trial.

    Science.gov (United States)

    Callahan, Christopher M; Boustani, Malaz A; Schmid, Arlene A; LaMantia, Michael A; Austrom, Mary G; Miller, Douglas K; Gao, Sujuan; Ferguson, Denisha Y; Lane, Kathleen A; Hendrie, Hugh C

    2017-02-07

    Alzheimer disease results in progressive functional decline, leading to loss of independence. To determine whether collaborative care plus 2 years of home-based occupational therapy delays functional decline. Randomized, controlled clinical trial. (ClinicalTrials.gov: NCT01314950). Urban public health system. 180 community-dwelling participants with Alzheimer disease and their informal caregivers. All participants received collaborative care for dementia. Patients in the intervention group also received in-home occupational therapy delivered in 24 sessions over 2 years. The primary outcome measure was the Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale (ADCS ADL); performance-based measures included the Short Physical Performance Battery (SPPB) and Short Portable Sarcopenia Measure (SPSM). At baseline, clinical characteristics did not differ significantly between groups; the mean Mini-Mental State Examination score for both groups was 19 (SD, 7). The intervention group received a median of 18 home visits from the study occupational therapists. In both groups, ADCS ADL scores declined over 24 months. At the primary end point of 24 months, ADCS ADL scores did not differ between groups (mean difference, 2.34 [95% CI, -5.27 to 9.96]). We also could not definitively demonstrate between-group differences in mean SPPB or SPSM values. The results of this trial are indeterminate and do not rule out potential clinically important effects of the intervention. The authors could not definitively demonstrate whether the addition of 2 years of in-home occupational therapy to a collaborative care management model slowed the rate of functional decline among persons with Alzheimer disease. This trial underscores the burden undertaken by caregivers as they provide care for family members with Alzheimer disease and the difficulty in slowing functional decline. National Institute on Aging.

  14. Effects of Mode of Target Task Selection on Learning about Plants in a Mobile Learning Environment: Effortful Manual Selection versus Effortless QR-Code Selection

    Science.gov (United States)

    Gao, Yuan; Liu, Tzu-Chien; Paas, Fred

    2016-01-01

    This study compared the effects of effortless selection of target plants using quick respond (QR) code technology to effortful manual search and selection of target plants on learning about plants in a mobile device supported learning environment. In addition, it was investigated whether the effectiveness of the 2 selection methods was…

  15. Generation of Aptamers from A Primer-Free Randomized ssDNA Library Using Magnetic-Assisted Rapid Aptamer Selection

    Science.gov (United States)

    Tsao, Shih-Ming; Lai, Ji-Ching; Horng, Horng-Er; Liu, Tu-Chen; Hong, Chin-Yih

    2017-04-01

    Aptamers are oligonucleotides that can bind to specific target molecules. Most aptamers are generated using random libraries in the standard systematic evolution of ligands by exponential enrichment (SELEX). Each random library contains oligonucleotides with a randomized central region and two fixed primer regions at both ends. The fixed primer regions are necessary for amplifying target-bound sequences by PCR. However, these extra-sequences may cause non-specific bindings, which potentially interfere with good binding for random sequences. The Magnetic-Assisted Rapid Aptamer Selection (MARAS) is a newly developed protocol for generating single-strand DNA aptamers. No repeat selection cycle is required in the protocol. This study proposes and demonstrates a method to isolate aptamers for C-reactive proteins (CRP) from a randomized ssDNA library containing no fixed sequences at 5‧ and 3‧ termini using the MARAS platform. Furthermore, the isolated primer-free aptamer was sequenced and binding affinity for CRP was analyzed. The specificity of the obtained aptamer was validated using blind serum samples. The result was consistent with monoclonal antibody-based nephelometry analysis, which indicated that a primer-free aptamer has high specificity toward targets. MARAS is a feasible platform for efficiently generating primer-free aptamers for clinical diagnoses.

  16. Emulsion PCR: a high efficient way of PCR amplification of random DNA libraries in aptamer selection.

    Directory of Open Access Journals (Sweden)

    Keke Shao

    Full Text Available Aptamers are short RNA or DNA oligonucleotides which can bind with different targets. Typically, they are selected from a large number of random DNA sequence libraries. The main strategy to obtain aptamers is systematic evolution of ligands by exponential enrichment (SELEX. Low efficiency is one of the limitations for conventional PCR amplification of random DNA sequence library in aptamer selection because of relative low products and high by-products formation efficiency. Here, we developed emulsion PCR for aptamer selection. With this method, the by-products formation decreased tremendously to an undetectable level, while the products formation increased significantly. Our results indicated that by-products in conventional PCR amplification were from primer-product and product-product hybridization. In emulsion PCR, we can completely avoid the product-product hybridization and avoid the most of primer-product hybridization if the conditions were optimized. In addition, it also showed that the molecule ratio of template to compartment was crucial to by-product formation efficiency in emulsion PCR amplification. Furthermore, the concentration of the Taq DNA polymerase in the emulsion PCR mixture had a significant impact on product formation efficiency. So, the results of our study indicated that emulsion PCR could improve the efficiency of SELEX.

  17. Microbial metabolomics: Replacing trial-and-error by the unbiased selection and ranking of targets

    NARCIS (Netherlands)

    Werf, M.J. van der; Jellema, R.H.; Hankemeier, T.

    2005-01-01

    Microbial production strains are currently improved using a combination of random and targeted approaches. In the case of a targeted approach, potential bottlenecks, feed-back inhibition, and side-routes are removed, and other processes of interest are targeted by overexpressing or knocking-out the

  18. Automated Threshold Selection for Template-Based Sonar Target Detection

    Science.gov (United States)

    2017-08-01

    Matched Filter Each matched filter mask contains three distinct regions: highlight, dead zone , and shadow/post- target. A different set of matched...and shadow zones . Both model both the targets and the backgrounds. Several methods have also used the fusion of multiple frequency bands to improve

  19. Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

    NARCIS (Netherlands)

    Vlot, A.H.C.; Witte, de W.E.A.; Danhof, M.; Graaf, van der P.H.; Westen, van G.J.P.; Lange, de E.C.M.

    2017-01-01

    Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable

  20. Event selection with a Random Forest in IceCube

    Energy Technology Data Exchange (ETDEWEB)

    Ruhe, Tim [TU, Dortmund (Germany); Collaboration: IceCube-Collaboration

    2011-07-01

    The Random Forest method is a multivariate algorithm that can be used for classification and regression respectively. The Random Forest implemented in the RapidMiner learning environment has been used for training and validation on data and Monte Carlo simulations of the IceCube neutrino telescope. Latest results are presented.

  1. Brief overview of selected approaches in targeting pancreatic adenocarcinoma.

    Science.gov (United States)

    Samore, Wesley R; Gondi, Christopher S

    2014-06-01

    Pancreatic adenocarcinoma (PDAC) has the worst prognosis of any major malignancy, with 5-year survival painfully inadequate at under 5%. Investigators have struggled to target and exploit PDAC unique biology, failing to bring meaningful results from bench to bedside. Nonetheless, in recent years, several promising targets have emerged. This review will discuss novel drug approaches in development for use in PDAC. The authors examine the continued efforts to target Kirsten rat sarcoma viral oncogene homolog (KRas), which have recently been successfully abated using novel small interfering RNA (siRNA) eluting devices. The authors also discuss other targets relevant to PDAC including those downstream of mutated KRas, such as MAPK kinase and phosphatidylinositol 3-kinase. Although studies into novel biomarkers and advanced imaging have highlighted the potential new avenues toward discovering localized tumors earlier, the current therapeutic options highlight the fact that PDAC is a highly metastatic and chemoresistant cancer that often must be fought with virulent, systemic therapies. Several newer approaches, including siRNA targeting of mutated KRas and enzymatic depletion of hyaluronan with PEGylated hyaluronidase are particularly exciting given their early stage results. Further research should help in elucidating their potential impact as therapeutic options.

  2. Reward priority of visual target singletons modulates ERP signatures of attentional selection

    Science.gov (United States)

    Kiss, Monika; Driver, Jon; Eimer, Martin

    2008-01-01

    We examined visual search for color singleton targets, whose shape was discriminated. Critically, we varied the reward priority of singleton colors (correct fast performance for red singletons was worth more “bonus points” than for green singletons, or vice-versa), while testing whether ERP signatures of visual selection can be affected by distinct reward priorities for different target types, even when every target has to be selected for report. The N2pc component was earlier and larger for high- versus low-reward targets. This reward influence on the N2pc correlated with the subject-by-subject impact of reward level on efficiency of behavioral performance. Later post-selection processing was also affected by target reward-level. These results demonstrate that visual selection of task-relevant item is rapidly modulated by reward-related priorities, even when both types of target have to be selected for response. PMID:19175756

  3. Fusion of Imperfect Information in the Unified Framework of Random Sets Theory: Application to Target Identification

    Science.gov (United States)

    2007-11-01

    droit du Canada), telle que représentée par le ministre de la Défense nationale, 2007 Abstract This is a study of the applicability of random sets...tracking and target identification, and non-military applications like medicine and robotics , have been developed using the mathematics of data fusion. The...been used in non-military applications such as robotics or medicine. The purpose of this section is to describe the target identification problem in

  4. Target selection for structural genomics of infectious diseases.

    Science.gov (United States)

    Yeats, Corin; Dessailly, Benoit H; Glass, Elizabeth M; Fremont, Daved H; Orengo, Christine A

    2014-01-01

    This chapter describes the protocols used to identify, filter, and annotate potential protein targets from an organism associated with infectious diseases. Protocols often combine computational approaches for mining information in public databases or for checking whether the protein has already been targeted for structure determination, with manual strategies that examine the literature for information on the biological role of the protein or the experimental strategies that explore the effects of knocking out the protein. Publicly available computational tools have been cited as much as possible. Where these do not exist, the concepts underlying in-house tools developed for the Center for Structural Genomics of Infectious Diseases have been described.

  5. Rapid selection of accessible and cleavable sites in RNA by Escherichia coli RNase P and random external guide sequences.

    Science.gov (United States)

    Lundblad, Eirik W; Xiao, Gaoping; Ko, Jae-Hyeong; Altman, Sidney

    2008-02-19

    A method of inhibiting the expression of particular genes by using external guide sequences (EGSs) has been improved in its rapidity and specificity. Random EGSs that have 14-nt random sequences are used in the selection procedure for an EGS that attacks the mRNA for a gene in a particular location. A mixture of the random EGSs, the particular target RNA, and RNase P is used in the diagnostic procedure, which, after completion, is analyzed in a gel with suitable control lanes. Within a few hours, the procedure is complete. The action of EGSs designed by an older method is compared with EGSs designed by the random EGS method on mRNAs from two bacterial pathogens.

  6. Regional personalized electrodes to select transcranial current stimulation target

    Directory of Open Access Journals (Sweden)

    Franca eTecchio

    2013-04-01

    Full Text Available Rationale Personalizing transcranial stimulations promises to enhance beneficial effects for individual patients.ObjectiveTo stimulate specific cortical regions by developing a procedure to bend and position custom shaped electrodes; to probe the effects on cortical excitability produced when the properly customized electrode is targeting different cortical areas.MethodAn ad-hoc neuronavigation procedure was developed to accurately shape and place the personalized electrodes on the basis of individual brain magnetic resonance images (MRI on bilateral primary motor (M1 and somatosensory (S1 cortices. The transcranial alternating current stimulation (tACS protocol published by Feurra and coll. (2011 was used to test the effects on cortical excitability of the personalized electrode when targeting S1 or M1.ResultsNeuronal excitability as evaluated by tACS was different when targeting M1 or S1, with the General Estimating Equation model indicating a clear tCS Effect (p < 0.001, and post-hoc comparisons showing solely M1 20Hz tACS to reduce M1 excitability with respect to baseline and other tACS conditions.ConclusionsThe present work indicates that specific cortical regions can be targeted by tCS properly shaping and positioning the stimulating electrode.SignificanceThrough multimodal brain investigations continuous efforts in understanding the neuronal changes related to specific neurological or psychiatric diseases become more relevant as our ability to build the compensating interventions improves. An important step forward on this path is the ability to target the specific cortical area of interest, as shown in the present pilot work.

  7. Study on MAX-MIN Ant System with Random Selection in Quadratic Assignment Problem

    Science.gov (United States)

    Iimura, Ichiro; Yoshida, Kenji; Ishibashi, Ken; Nakayama, Shigeru

    Ant Colony Optimization (ACO), which is a type of swarm intelligence inspired by ants' foraging behavior, has been studied extensively and its effectiveness has been shown by many researchers. The previous studies have reported that MAX-MIN Ant System (MMAS) is one of effective ACO algorithms. The MMAS maintains the balance of intensification and diversification concerning pheromone by limiting the quantity of pheromone to the range of minimum and maximum values. In this paper, we propose MAX-MIN Ant System with Random Selection (MMASRS) for improving the search performance even further. The MMASRS is a new ACO algorithm that is MMAS into which random selection was newly introduced. The random selection is one of the edgechoosing methods by agents (ants). In our experimental evaluation using ten quadratic assignment problems, we have proved that the proposed MMASRS with the random selection is superior to the conventional MMAS without the random selection in the viewpoint of the search performance.

  8. Random Access Memories: A New Paradigm for Target Detection in High Resolution Aerial Remote Sensing Images.

    Science.gov (United States)

    Zou, Zhengxia; Shi, Zhenwei

    2018-03-01

    We propose a new paradigm for target detection in high resolution aerial remote sensing images under small target priors. Previous remote sensing target detection methods frame the detection as learning of detection model + inference of class-label and bounding-box coordinates. Instead, we formulate it from a Bayesian view that at inference stage, the detection model is adaptively updated to maximize its posterior that is determined by both training and observation. We call this paradigm "random access memories (RAM)." In this paradigm, "Memories" can be interpreted as any model distribution learned from training data and "random access" means accessing memories and randomly adjusting the model at detection phase to obtain better adaptivity to any unseen distribution of test data. By leveraging some latest detection techniques e.g., deep Convolutional Neural Networks and multi-scale anchors, experimental results on a public remote sensing target detection data set show our method outperforms several other state of the art methods. We also introduce a new data set "LEarning, VIsion and Remote sensing laboratory (LEVIR)", which is one order of magnitude larger than other data sets of this field. LEVIR consists of a large set of Google Earth images, with over 22 k images and 10 k independently labeled targets. RAM gives noticeable upgrade of accuracy (an mean average precision improvement of 1% ~ 4%) of our baseline detectors with acceptable computational overhead.

  9. Distributed Detection of Randomly Located Targets in Mobility-Assisted Sensor Networks with Node Mobility Management

    Directory of Open Access Journals (Sweden)

    Jayaweera SudharmanK

    2010-01-01

    Full Text Available Performance gain achieved by adding mobile nodes to a stationary sensor network for target detection depends on factors such as the number of mobile nodes deployed, mobility patterns, speed and energy constraints of mobile nodes, and the nature of the target locations (deterministic or random. In this paper, we address the problem of distributed detection of a randomly located target by a hybrid sensor network. Specifically, we develop two decision-fusion architectures for detection where in the first one, impact of node mobility is taken into account for decisions updating at the fusion center, while in the second model the impact of node mobility is taken at the node level decision updating. The cost of deploying mobile nodes is analyzed in terms of the minimum fraction of mobile nodes required to achieve the desired performance level within a desired delay constraint. Moreover, we consider managing node mobility under given constraints.

  10. Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes.

    NARCIS (Netherlands)

    de Groote, M.L.; Verschure, P.J.; Rots, M.G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  11. Epigenetic Editing : targeted rewriting of epigenetic marks to modulate expression of selected target genes

    NARCIS (Netherlands)

    de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  12. Signal Transduction and Molecular Targets of Selected Flavonoids

    Science.gov (United States)

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  13. Structural genomics target selection for the New York consortium on membrane protein structure.

    Science.gov (United States)

    Punta, Marco; Love, James; Handelman, Samuel; Hunt, John F; Shapiro, Lawrence; Hendrickson, Wayne A; Rost, Burkhard

    2009-12-01

    The New York Consortium on Membrane Protein Structure (NYCOMPS), a part of the Protein Structure Initiative (PSI) in the USA, has as its mission to establish a high-throughput pipeline for determination of novel integral membrane protein structures. Here we describe our current target selection protocol, which applies structural genomics approaches informed by the collective experience of our team of investigators. We first extract all annotated proteins from our reagent genomes, i.e. the 96 fully sequenced prokaryotic genomes from which we clone DNA. We filter this initial pool of sequences and obtain a list of valid targets. NYCOMPS defines valid targets as those that, among other features, have at least two predicted transmembrane helices, no predicted long disordered regions and, except for community nominated targets, no significant sequence similarity in the predicted transmembrane region to any known protein structure. Proteins that feed our experimental pipeline are selected by defining a protein seed and searching the set of all valid targets for proteins that are likely to have a transmembrane region structurally similar to that of the seed. We require sequence similarity aligning at least half of the predicted transmembrane region of seed and target. Seeds are selected according to their feasibility and/or biological interest, and they include both centrally selected targets and community nominated targets. As of December 2008, over 6,000 targets have been selected and are currently being processed by the experimental pipeline. We discuss how our target list may impact structural coverage of the membrane protein space.

  14. In Vitro Selection and Characterization of DNA Aptamers to a Small Molecule Target.

    Science.gov (United States)

    Ruscito, Annamaria; McConnell, Erin M; Koudrina, Anna; Velu, Ranganathan; Mattice, Christopher; Hunt, Vernon; McKeague, Maureen; DeRosa, Maria C

    2017-12-14

    Aptamers, synthetic oligonucleotide-based molecular recognition probes, have found use in a wide array of biosensing technologies based on their tight and highly selective binding to a variety of molecular targets. However, the inherent challenges associated with the selection and characterization of aptamers for small molecule targets have resulted in their underrepresentation, despite the need for small molecule detection in fields such as medicine, the environment, and agriculture. This protocol describes the steps in the selection, sequencing, affinity characterization, and truncation of DNA aptamers that are specific for small molecule targets. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  15. In vivo selection of randomly mutated retroviral genomes

    NARCIS (Netherlands)

    Berkhout, B.; Klaver, B.

    1993-01-01

    Darwinian evolution, that is the outgrowth of the fittest variants in a population, usually applies to living organisms over long periods of time. Recently, in vitro selection/amplification techniques have been developed that allow for the rapid evolution of functionally active nucleic acids from a

  16. Chemical tools selectively target components of the PKA system

    Directory of Open Access Journals (Sweden)

    Drewianka Stephan

    2009-02-01

    Full Text Available Abstract Background In the eukaryotic cell the cAMP-dependent protein kinase (PKA is a key enzyme in signal transduction and represents the main target of the second messenger cAMP. Here we describe the design, synthesis and characterisation of specifically tailored cAMP analogs which can be utilised as a tool for affinity enrichment and purification as well as for proteomics based analyses of cAMP binding proteins. Results Two sets of chemical binders were developed based on the phosphorothioate derivatives of cAMP, Sp-cAMPS and Rp-cAMPS acting as cAMP-agonists and -antagonists, respectively. These compounds were tested via direct surface plasmon resonance (SPR analyses for their binding properties to PKA R-subunits and holoenzyme. Furthermore, these analogs were used in an affinity purification approach to analyse their binding and elution properties for the enrichment and improvement of cAMP binding proteins exemplified by the PKA R-subunits. As determined by SPR, all tested Sp-analogs provide valuable tools for affinity chromatography. However, Sp-8-AEA-cAMPS displayed (i superior enrichment properties while maintaining low unspecific binding to other proteins in crude cell lysates, (ii allowing mild elution conditions and (iii providing the capability to efficiently purify all four isoforms of active PKA R-subunit in milligram quantities within 8 h. In a chemical proteomics approach both sets of binders, Rp- and Sp-cAMPS derivatives, can be employed. Whereas Sp-8-AEA-cAMPS preferentially binds free R-subunit, Rp-AHDAA-cAMPS, displaying antagonist properties, not only binds to the free PKA R-subunits but also to the intact PKA holoenzyme both from recombinant and endogenous sources. Conclusion In summary, all tested cAMP analogs were useful for their respective application as an affinity reagent which can enhance purification of cAMP binding proteins. Sp-8-AEA-cAMPS was considered the most efficient analog since Sp-8-AHA-cAMPS and Sp-2-AHA

  17. Assessing the accuracy and stability of variable selection methods for random forest modeling in ecology

    Science.gov (United States)

    Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological datasets there is limited guidance on variable selection methods for RF modeling. Typically, e...

  18. The frequency of drugs in randomly selected drivers in Denmark

    DEFF Research Database (Denmark)

    Simonsen, Kirsten Wiese; Steentoft, Anni; Hels, Tove

    Introduction Driving under the influence of alcohol and drugs is a global problem. In Denmark as well as in other countries there is an increasing focus on impaired driving. Little is known about the occurrence of psychoactive drugs in the general traffic. Therefore the European commission...... initiated the DRUID project. This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Methods Oral fluid samples (n = 3002) were collected randomly from drivers using a sampling scheme...... stratified by time, season, and road type. The oral fluid samples were screened for 29 illegal and legal psychoactive substances and metabolites as well as ethanol. Results Fourteen (0.5%) drivers were positive for ethanol (alone or in combination with drugs) at concentrations above 0.53 g/l, which...

  19. Sample Selection in Randomized Experiments: A New Method Using Propensity Score Stratified Sampling

    Science.gov (United States)

    Tipton, Elizabeth; Hedges, Larry; Vaden-Kiernan, Michael; Borman, Geoffrey; Sullivan, Kate; Caverly, Sarah

    2014-01-01

    Randomized experiments are often seen as the "gold standard" for causal research. Despite the fact that experiments use random assignment to treatment conditions, units are seldom selected into the experiment using probability sampling. Very little research on experimental design has focused on how to make generalizations to well-defined…

  20. Pseudo cluster randomization dealt with selection bias and contamination in clinical trials

    NARCIS (Netherlands)

    Teerenstra, S.; Melis, R.J.F.; Peer, P.G.M.; Borm, G.F.

    2006-01-01

    BACKGROUND AND OBJECTIVES: When contamination is present, randomization on a patient level leads to dilution of the treatment effect. The usual solution is to randomize on a cluster level, but at the cost of efficiency and more importantly, this may introduce selection bias. Furthermore, it may slow

  1. Coping with Atmospheric Turbulence in the Selection of Laser Hardening Technology for FCS Targeting Systems

    National Research Council Canada - National Science Library

    Pritchett, Timothy M

    2004-01-01

    ... by frequency-agile battlefield lasers at both long and short range. Evidently, the selection of sensor protection technologies for incorporation into the final targeting system will be based on their optical limiting performance under field conditions...

  2. Automatic Target Recognition: Statistical Feature Selection of Non-Gaussian Distributed Target Classes

    Science.gov (United States)

    2011-06-01

    SequentialForwardSelection_Hellinger(class1,class2,NumFeatComb) %%% SFS Algorithm---Best is the vector of the best subset GSF =1.1; dX=.1; NofFeatures=size... GSF ,dX); f_class1=KDE_MJW(class1(:,combi),GridCell); f_class2=KDE_MJW(class2(:,combi),GridCell); f_class1N=Normalize_PDF

  3. Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Vera L Silva

    Full Text Available The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy.

  4. Target-object integration, attention distribution, and object orientation interactively modulate object-based selection.

    Science.gov (United States)

    Al-Janabi, Shahd; Greenberg, Adam S

    2016-10-01

    The representational basis of attentional selection can be object-based. Various studies have suggested, however, that object-based selection is less robust than spatial selection across experimental paradigms. We sought to examine the manner by which the following factors might explain this variation: Target-Object Integration (targets 'on' vs. part 'of' an object), Attention Distribution (narrow vs. wide), and Object Orientation (horizontal vs. vertical). In Experiment 1, participants discriminated between two targets presented 'on' an object in one session, or presented as a change 'of' an object in another session. There was no spatial cue-thus, attention was initially focused widely-and the objects were horizontal or vertical. We found evidence of object-based selection only when targets constituted a change 'of' an object. Additionally, object orientation modulated the sign of object-based selection: We observed a same-object advantage for horizontal objects, but a same-object cost for vertical objects. In Experiment 2, an informative cue preceded a single target presented 'on' an object or as a change 'of' an object (thus, attention was initially focused narrowly). Unlike in Experiment 1, we found evidence of object-based selection independent of target-object integration. We again found that the sign of selection was modulated by the objects' orientation. This result may reflect a meridian effect, which emerged due to anisotropies in the cortical representations when attention is oriented endogenously. Experiment 3 revealed that object orientation did not modulate object-based selection when attention was oriented exogenously. Our findings suggest that target-object integration, attention distribution, and object orientation modulate object-based selection, but only in combination.

  5. Evaluating gaze-based interface tools to facilitate point-and-select tasks with small targets

    DEFF Research Database (Denmark)

    Skovsgaard, Henrik; Mateo, Julio C.; Hansen, John Paulin

    2011-01-01

    Gaze interaction affords hands-free control of computers. Pointing to and selecting small targets using gaze alone is difficult because of the limited accuracy of gaze pointing. This is the first experimental comparison of gaze-based interface tools for small-target (e.g. <12 × 12 pixels) point-a...

  6. Acceptance sampling using judgmental and randomly selected samples

    Energy Technology Data Exchange (ETDEWEB)

    Sego, Landon H.; Shulman, Stanley A.; Anderson, Kevin K.; Wilson, John E.; Pulsipher, Brent A.; Sieber, W. Karl

    2010-09-01

    We present a Bayesian model for acceptance sampling where the population consists of two groups, each with different levels of risk of containing unacceptable items. Expert opinion, or judgment, may be required to distinguish between the high and low-risk groups. Hence, high-risk items are likely to be identifed (and sampled) using expert judgment, while the remaining low-risk items are sampled randomly. We focus on the situation where all observed samples must be acceptable. Consequently, the objective of the statistical inference is to quantify the probability that a large percentage of the unsampled items in the population are also acceptable. We demonstrate that traditional (frequentist) acceptance sampling and simpler Bayesian formulations of the problem are essentially special cases of the proposed model. We explore the properties of the model in detail, and discuss the conditions necessary to ensure that required samples sizes are non-decreasing function of the population size. The method is applicable to a variety of acceptance sampling problems, and, in particular, to environmental sampling where the objective is to demonstrate the safety of reoccupying a remediated facility that has been contaminated with a lethal agent.

  7. Disclosing the Parameters Leading to High Productivity of Retroviral Producer Cells Lines: Evaluating Random Versus Targeted Integration.

    Science.gov (United States)

    Bandeira, Vanessa S; Tomás, Hélio A; Alici, Evren; Carrondo, Manuel J T; Coroadinha, Ana S

    2017-04-01

    Gammaretrovirus and lentivirus are the preferred viral vectors to genetically modify T and natural killer cells to be used in immune cell therapies. The transduction efficiency of hematopoietic and T cells is more efficient using gibbon ape leukemia virus (GaLV) pseudotyping. In this context gammaretroviral vector producer cells offer competitive higher titers than transient lentiviral vectors productions. The main aim of this work was to identify the key parameters governing GaLV-pseudotyped gammaretroviral vector productivity in stable producer cells, using a retroviral vector expression cassette enabling positive (facilitating cell enrichment) and negative cell selection (allowing cell elimination). The retroviral vector contains a thymidine kinase suicide gene fused with a ouabain-resistant Na + ,K + -ATPase gene, a potential safer and faster marker. The establishment of retroviral vector producer cells is traditionally performed by randomly integrating the retroviral vector expression cassette codifying the transgene. More recently, recombinase-mediated cassette exchange methodologies have been introduced to achieve targeted integration. Herein we compared random and targeted integration of the retroviral vector transgene construct. Two retroviral producer cell lines, 293 OuaS and 293 FlexOuaS, were generated by random and targeted integration, respectively, producing high titers (on the order of 10 7 infectious particles·ml -1 ). Results showed that the retroviral vector transgene cassette is the key retroviral vector component determining the viral titers notwithstanding, single-copy integration is sufficient to provide high titers. The expression levels of the three retroviral constructs (gag-pol, GaLV env, and retroviral vector transgene) were analyzed. Although gag-pol and GaLV env gene expression levels should surpass a minimal threshold, we found that relatively modest expression levels of these two expression cassettes are required. Their levels of

  8. Influence of target concentration and background binding on in vitro selection of affinity reagents.

    Directory of Open Access Journals (Sweden)

    Jinpeng Wang

    Full Text Available Nucleic acid-based aptamers possess many useful features that make them a promising alternative to antibodies and other affinity reagents, including well-established chemical synthesis, reversible folding, thermal stability and low cost. However, the selection process typically used to generate aptamers (SELEX often requires significant resources and can fail to yield aptamers with sufficient affinity and specificity. A number of seminal theoretical models and numerical simulations have been reported in the literature offering insights into experimental factors that govern the effectiveness of the selection process. Though useful, these previous models have not considered the full spectrum of experimental factors or the potential impact of tuning these parameters at each round over the course of a multi-round selection process. We have developed an improved mathematical model to address this important question, and report that both target concentration and the degree of non-specific background binding are critical determinants of SELEX efficiency. Although smaller target concentrations should theoretically offer superior selection outcome, we show that the level of background binding dramatically affect the target concentration that will yield maximum enrichment at each round of selection. Thus, our model enables experimentalists to determine appropriate target concentrations as a means for protocol optimization. Finally, we perform a comparative analysis of two different selection methods over multiple rounds of selection, and show that methods with inherently lower background binding offer dramatic advantages in selection efficiency.

  9. Quantifying the Tendency of Therapeutic Target Proteins to Bind Promiscuous or Selective Compounds

    Science.gov (United States)

    Hu, Ye; Bajorath, Jürgen

    2015-01-01

    The ability of target proteins to bind structurally diverse compounds and compounds with different degrees of promiscuity (multi-target activity) was systematically assessed on the basis of currently available activity data and target annotations. Intuitive first- and second-order target promiscuity indices were introduced to quantify these binding characteristics and relate them to each other. For compounds and targets, opposite promiscuity trends were observed. Furthermore, the analysis detected many targets that interacted with compounds representing a similar degree of structural diversity but displayed strong tendencies to recognize either promiscuous or selective compounds. Moreover, target families were identified that preferentially interacted with promiscuous compounds. Taken together, these findings further extend our understanding of the molecular basis of polypharmacology. PMID:26000736

  10. RANDOM FORESTS-BASED FEATURE SELECTION FOR LAND-USE CLASSIFICATION USING LIDAR DATA AND ORTHOIMAGERY

    Directory of Open Access Journals (Sweden)

    H. Guan

    2012-07-01

    Full Text Available The development of lidar system, especially incorporated with high-resolution camera components, has shown great potential for urban classification. However, how to automatically select the best features for land-use classification is challenging. Random Forests, a newly developed machine learning algorithm, is receiving considerable attention in the field of image classification and pattern recognition. Especially, it can provide the measure of variable importance. Thus, in this study the performance of the Random Forests-based feature selection for urban areas was explored. First, we extract features from lidar data, including height-based, intensity-based GLCM measures; other spectral features can be obtained from imagery, such as Red, Blue and Green three bands, and GLCM-based measures. Finally, Random Forests is used to automatically select the optimal and uncorrelated features for landuse classification. 0.5-meter resolution lidar data and aerial imagery are used to assess the feature selection performance of Random Forests in the study area located in Mannheim, Germany. The results clearly demonstrate that the use of Random Forests-based feature selection can improve the classification performance by the selected features.

  11. Pro and cons of targeted selective treatment against digestive-tract strongyles of ruminants.

    Science.gov (United States)

    Cabaret, J

    2008-09-01

    The increasing prevalence of resistance to anthelmintics among gastrointestinal nematodes and the desire for lower input agriculture have promoted the idea that targeted selective treatment (treating the animals in need of such a treatment and only them) could be a sustainable solution for controlling internal parasites of ruminants. The pros are the slowing of resistance prevalence, lower residues of anthelmintics in meat and milk, and lower cost; the cons are the difficulty and time spent on selecting animals in need of treatment and the possibility of lower production. Using actual experiments and modelling we show that targeted selective treatment can be used to sustainably control gastrointestinal nematode infections in flock.

  12. Pro and cons of targeted selective treatment against digestive-tract strongyles of ruminants

    Directory of Open Access Journals (Sweden)

    Cabaret J.

    2008-09-01

    Full Text Available The increasing prevalence of resistance to anthelmintics among gastrointestinal nematodes and the desire for lower input agriculture have promoted the idea that targeted selective treatment (treating the animals in need of such a treatment and only them could be a sustainable solution for controlling internal parasites of ruminants. The pros are the slowing of resistance prevalence, lower residues of anthelmintics in meat and milk, and lower cost; the cons are the difficulty and time spent on selecting animals in need of treatment and the possibility of lower production. Using actual experiments and modelling we show that targeted selective treatment can be used to sustainably control gastrointestinal nematode infections in flock.

  13. Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses.

    Science.gov (United States)

    Lammers, Jeroen; Goossens, Ferry; Conrod, Patricia; Engels, Rutger; Wiers, Reinout W; Kleinjan, Marloes

    2017-08-01

    To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. A clustered randomized controlled trial, with participants randomly assigned to a 2-session coping skills intervention or a control no-intervention condition. Fifteen secondary schools throughout The Netherlands; 7 schools in the intervention and 8 schools in the control condition. 699 adolescents aged 13-15; 343 allocated to the intervention and 356 to the control condition; with drinking experience and elevated scores in either negative thinking, anxiety sensitivity, impulsivity or sensation seeking. Differential effectiveness of the Preventure program was examined for the personality traits group, education level and gender on past-month binge drinking (main outcome), binge frequency, alcohol use, alcohol frequency and problem drinking, at 12months post-intervention. Preventure is a selective school-based alcohol prevention programme targeting personality risk factors. The comparator was a no-intervention control. Intervention effects were moderated by the personality traits group and by education level. More specifically, significant intervention effects were found on reducing alcohol use within the anxiety sensitivity group (OR=2.14, CI=1.40, 3.29) and reducing binge drinking (OR=1.76, CI=1.38, 2.24) and binge drinking frequency (β=0.24, p=0.04) within the sensation seeking group at 12months post-intervention. Also, lower educated young adolescents reduced binge drinking (OR=1.47, CI=1.14, 1.88), binge drinking frequency (β=0.25, p=0.04), alcohol use (OR=1.32, CI=1.06, 1.65) and alcohol use frequency (β=0.47, p=0.01), but not those in the higher education group. Post hoc latent-growth analyses revealed significant effects on the development of binge drinking (β=-0.19, p=0.02) and binge drinking frequency (β=-0.10, p=0

  14. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

    Directory of Open Access Journals (Sweden)

    Stefania Monteleone

    2017-08-01

    Full Text Available Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015 have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process

  15. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity.

    Science.gov (United States)

    Monteleone, Stefania; Fuchs, Julian E; Liedl, Klaus R

    2017-01-01

    Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015) have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels) shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process. Additionally

  16. The impact of hotspot-targeted interventions on malaria transmission: study protocol for a cluster-randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Bousema Teun

    2013-02-01

    Full Text Available Abstract Background Malaria transmission is highly heterogeneous in most settings, resulting in the formation of recognizable malaria hotspots. Targeting these hotspots might represent a highly efficacious way of controlling or eliminating malaria if the hotspots fuel malaria transmission to the wider community. Methods/design Hotspots of malaria will be determined based on spatial patterns in age-adjusted prevalence and density of antibodies against malaria antigens apical membrane antigen-1 and merozoite surface protein-1. The community effect of interventions targeted at these hotspots will be determined. The intervention will comprise larviciding, focal screening and treatment of the human population, distribution of long-lasting insecticide-treated nets and indoor residual spraying. The impact of the intervention will be determined inside and up to 500 m outside the targeted hotspots by PCR-based parasite prevalence in cross-sectional surveys, malaria morbidity by passive case detection in selected facilities and entomological monitoring of larval and adult Anopheles populations. Discussion This study aims to provide direct evidence for a community effect of hotspot-targeted interventions. The trial is powered to detect large effects on malaria transmission in the context of ongoing malaria interventions. Follow-up studies will be needed to determine the effect of individual components of the interventions and the cost-effectiveness of a hotspot-targeted approach, where savings made by reducing the number of compounds that need to receive interventions should outweigh the costs of hotspot-detection. Trial registration NCT01575613. The protocol was registered online on 20 March 2012; the first community was randomized on 26 March 2012.

  17. Target decoupling in a coupled optical system resistant to random perturbation

    CERN Document Server

    Yu, Sunkyu; Park, Namkyoo

    2016-01-01

    To suppress unwanted crosstalks between nearby optical elements, the decoupling technique for integrated systems has been desired for the target control of light flows. Although cloaking methods have enabled complete decoupling of optical elements by manipulating electromagnetic waves microscopically, it is neither feasible nor necessary to control each unit element in coupled systems when considering severe restrictions on material parameters for cloaking. Here we develop the macroscopic approach to design crosstalk-free regions in coupled optical systems. By inversely designing the eigenstate which encompasses target elements, the stable decoupling of the elements from the coupled system is achieved, being completely independent from the random alteration of the decoupled region, and at the same time, allowing coherent and scattering-free wave transport with desired spatial profiles. We also demonstrate the decoupling in disordered systems, overcoming the transport blockade from Anderson localization. Our r...

  18. Target Temperature Management after out-of-hospital cardiac arrest--a randomized, parallel-group, assessor-blinded clinical trial--rationale and design

    DEFF Research Database (Denmark)

    Nielsen, Niklas; Wetterslev, Jørn; al-Subaie, Nawaf

    2012-01-01

    Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation...... from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia...... in the control groups. The optimal target temperature management strategy is not known....

  19. [,Targeted' and 'targeted selective treatments' in goats: Evaluation of several decision criteria and development of a practical decision key].

    Science.gov (United States)

    Bollinger, J; Hertzberg, H; Hässig, M; Knubben-Schweizer, G

    2016-08-01

    The aim of the study was to get an overview of control measures against gastrointestinal nematodes in goats in Switzerland. Based on the answers to a questionnaire, we assessed the readiness of owners to use targeted or targeted selective treatment, and to develop a practical decision tool for the indication of treatment of individual animals. The results show that the number of treatments per year decreased compared to previous studies. Furthermore, the survey shows that a large proportion of goat farmers (73.9%) is willing to change the present treatment strategy. A simple decision key based on the evaluation of body condition, the consistency of the faeces and the degree of the anaemia (FAMACHA©) was tested in a field survey. It could be shown that goat owners are able to carry out the simple protocol reliably on their own and correctly evaluate individuals regarding their need of treatment.

  20. SNP selection and classification of genome-wide SNP data using stratified sampling random forests.

    Science.gov (United States)

    Wu, Qingyao; Ye, Yunming; Liu, Yang; Ng, Michael K

    2012-09-01

    For high dimensional genome-wide association (GWA) case-control data of complex disease, there are usually a large portion of single-nucleotide polymorphisms (SNPs) that are irrelevant with the disease. A simple random sampling method in random forest using default mtry parameter to choose feature subspace, will select too many subspaces without informative SNPs. Exhaustive searching an optimal mtry is often required in order to include useful and relevant SNPs and get rid of vast of non-informative SNPs. However, it is too time-consuming and not favorable in GWA for high-dimensional data. The main aim of this paper is to propose a stratified sampling method for feature subspace selection to generate decision trees in a random forest for GWA high-dimensional data. Our idea is to design an equal-width discretization scheme for informativeness to divide SNPs into multiple groups. In feature subspace selection, we randomly select the same number of SNPs from each group and combine them to form a subspace to generate a decision tree. The advantage of this stratified sampling procedure can make sure each subspace contains enough useful SNPs, but can avoid a very high computational cost of exhaustive search of an optimal mtry, and maintain the randomness of a random forest. We employ two genome-wide SNP data sets (Parkinson case-control data comprised of 408 803 SNPs and Alzheimer case-control data comprised of 380 157 SNPs) to demonstrate that the proposed stratified sampling method is effective, and it can generate better random forest with higher accuracy and lower error bound than those by Breiman's random forest generation method. For Parkinson data, we also show some interesting genes identified by the method, which may be associated with neurological disorders for further biological investigations.

  1. An efficient method of wavelength interval selection based on random frog for multivariate spectral calibration

    Science.gov (United States)

    Yun, Yong-Huan; Li, Hong-Dong; Wood, Leslie R. E.; Fan, Wei; Wang, Jia-Jun; Cao, Dong-Sheng; Xu, Qing-Song; Liang, Yi-Zeng

    2013-07-01

    Wavelength selection is a critical step for producing better prediction performance when applied to spectral data. Considering the fact that the vibrational and rotational spectra have continuous features of spectral bands, we propose a novel method of wavelength interval selection based on random frog, called interval random frog (iRF). To obtain all the possible continuous intervals, spectra are first divided into intervals by moving window of a fix width over the whole spectra. These overlapping intervals are ranked applying random frog coupled with PLS and the optimal ones are chosen. This method has been applied to two near-infrared spectral datasets displaying higher efficiency in wavelength interval selection than others. The source code of iRF can be freely downloaded for academy research at the website: http://code.google.com/p/multivariate-calibration/downloads/list.

  2. Victims' routine activities and sex offenders' target selection scripts: a latent class analysis.

    Science.gov (United States)

    Deslauriers-Varin, Nadine; Beauregard, Eric

    2010-09-01

    This study investigates target selection scripts of 72 serial sex offenders who have committed a total of 361 sex crimes on stranger victims. Using latent class analysis, three target selection scripts were identified based on the victim's activities prior to the crime, each presenting two different tracks: (1) the Home script, which includes the (a) intrusion track and the (b) invited track, (2) the Outdoor script, which includes the (a) noncoercive track and the (b) coercive track, and (3) the Social script, which includes the (a) onsite track and the (b) off-site track. The scripts identified appeared to be used by both sexual aggressors of children and sexual aggressors of adults. In addition, a high proportion of crime switching was found among the identified scripts, with half of the 72 offenders switching scripts at least once. The theoretical relevance of these target selection scripts and their practical implications for situational crime prevention strategies are discussed.

  3. Delay line length selection in generating fast random numbers with a chaotic laser.

    Science.gov (United States)

    Zhang, Jianzhong; Wang, Yuncai; Xue, Lugang; Hou, Jiayin; Zhang, Beibei; Wang, Anbang; Zhang, Mingjiang

    2012-04-10

    The chaotic light signals generated by an external cavity semiconductor laser have been experimentally demonstrated to extract fast random numbers. However, the photon round-trip time in the external cavity can cause the occurrence of the periodicity in random sequences. To overcome it, the exclusive-or operation on corresponding random bits in samples of the chaotic signal and its time-delay signal from a chaotic laser is required. In this scheme, the proper selection of delay length is a key issue. By doing a large number of experiments and theoretically analyzing the interplay between the Runs test and the threshold value of the autocorrelation function, we find when the corresponding delay time of autocorrelation trace with the correlation coefficient of less than 0.007 is considered as the delay time between the chaotic signal and its time-delay signal, streams of random numbers can be generated with verified randomness.

  4. Novel random peptide libraries displayed on AAV serotype 9 for selection of endothelial cell-directed gene transfer vectors.

    Science.gov (United States)

    Varadi, K; Michelfelder, S; Korff, T; Hecker, M; Trepel, M; Katus, H A; Kleinschmidt, J A; Müller, O J

    2012-08-01

    We have demonstrated the potential of random peptide libraries displayed on adeno-associated virus (AAV)2 to select for AAV2 vectors with improved efficiency for cell type-directed gene transfer. AAV9, however, may have advantages over AAV2 because of a lower prevalence of neutralizing antibodies in humans and more efficient gene transfer in vivo. Here we provide evidence that random peptide libraries can be displayed on AAV9 and can be utilized to select for AAV9 capsids redirected to the cell type of interest. We generated an AAV9 peptide display library, which ensures that the displayed peptides correspond to the packaged genomes and performed four consecutive selection rounds on human coronary artery endothelial cells in vitro. This screening yielded AAV9 library capsids with distinct peptide motifs enabling up to 40-fold improved transduction efficiencies compared with wild-type (wt) AAV9 vectors. Incorporating sequences selected from AAV9 libraries into AAV2 capsids could not increase transduction as efficiently as in the AAV9 context. To analyze the potential on endothelial cells in the intact natural vascular context, human umbilical veins were incubated with the selected AAV in situ and endothelial cells were isolated. Fluorescence-activated cell sorting analysis revealed a 200-fold improved transduction efficiency compared with wt AAV9 vectors. Furthermore, AAV9 vectors with targeting sequences selected from AAV9 libraries revealed an increased transduction efficiency in the presence of human intravenous immunoglobulins, suggesting a reduced immunogenicity. We conclude that our novel AAV9 peptide library is functional and can be used to select for vectors for future preclinical and clinical gene transfer applications.

  5. Social exclusion impairs distractor suppression but not target enhancement in selective attention.

    Science.gov (United States)

    Xu, Mengsi; Li, Zhiai; Diao, Liuting; Fan, Lingxia; Zhang, Lijie; Yuan, Shuge; Yang, Dong

    2017-11-01

    Social exclusion has been thought to weaken one's ability to exert inhibitory control. Existing studies have primarily focused on the relationship between exclusion and behavioral inhibition, and have reported that exclusion impairs behavioral inhibition. However, whether exclusion also affects selective attention, another important aspect of inhibitory control, remains unknown. Therefore, the current study aimed to explore whether social exclusion impairs selective attention, and to specifically examine its effect on two hypothesized mechanisms of selective attention: target enhancement and distractor suppression. The Cyberball game was used to manipulate social exclusion. Participants then performed a visual search task while event-related potentials were recorded. In the visual search task, target and salient distractor were either both presented laterally or one was presented on the vertical midline and the other laterally. Results showed that social exclusion differentially affected target and distractor processing. While exclusion impaired distractor suppression, reflected as smaller distractor-positivity (Pd) amplitudes for the exclusion group compared to the inclusion group, it did not affect target enhancement, reflected as similar target-negativity (Nt) amplitudes for both the exclusion and inclusion groups. Together, these results extend our understanding of the relationship between exclusion and inhibitory control, and suggest that social exclusion affects selective attention in a more complex manner than previously thought. Copyright © 2017. Published by Elsevier B.V.

  6. A brief randomized controlled intervention targeting parents improves grades during middle school.

    Science.gov (United States)

    Destin, Mesmin; Svoboda, Ryan C

    2017-04-01

    Despite a growing number of brief, psychosocial interventions that improve academic achievement, little research investigates how to leverage parents during such efforts. We designed and tested a randomized controlled intervention targeting parents to influence important discussions about the future and responses to academic difficulty experienced by their adolescent during eighth grade in the United States. We recruited experienced parents to convey the main messages of the intervention in a parent panel format. As expected, current parents who were randomly assigned to observe the parent panel subsequently planned to talk with their adolescents sooner about future opportunities and to respond more positively to experiences of academic difficulty than parents who were randomly assigned to a control group. The intervention also led to a significant increase in student grades, which was mediated by parents' responses to academic difficulty. We suggest an increase in experimental research that utilizes parents to influence student achievement. Copyright © 2017 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  7. Selective attention modulates the effect of target location probability on redundant signal processing.

    Science.gov (United States)

    Chang, Ting-Yun; Little, Daniel R; Yang, Cheng-Ta

    2016-08-01

    We investigated the decision process underlying the detection of targets at multiple locations. In three experiments using the same observers, target location probability and attentional instructions were manipulated. A redundant-target detection task was conducted in which participants were required to detect a dot presented at one of two locations. When the dot appeared at the two locations with equal frequency (Experiment 1), those participants who were found to have limited to unlimited capacity were shown to adopt a parallel, self-terminating strategy. By contrast, those participants who had supercapacity were shown to process redundant targets in a coactive manner. When targets were presented with unequal probability, two participants adopted a parallel, self-terminating strategy regardless of whether they were informed the target location probability (Experiment 3) or not (Experiment 2). For the remaining two participants, the strategy changed from parallel, self-terminating to serial, self-terminating as a result of the probability instructions. In Experiments 2 and 3, all the participants were of unlimited to limited capacity. Taken together, these results suggest that target location probability differently affects the selection of a decision strategy and highlight the role of controlled attention in selecting a decision strategy.

  8. TARPARE: a method for selecting target audiences for public health interventions.

    Science.gov (United States)

    Donovan, R J; Egger, G; Francas, M

    1999-06-01

    This paper presents a model to assist the health promotion practitioner systematically compare and select what might be appropriate target groups when there are a number of segments competing for attention and resources. TARPARE assesses previously identified segments on the following criteria: T: The Total number of persons in the segment; AR: The proportion of At Risk persons in the segment; P: The Persuability of the target audience; A: The Accessibility of the target audience; R: Resources required to meet the needs of the target audience; and E: Equity, social justice considerations. The assessment can be applied qualitatively or can be applied such that scores can be assigned to each segment. Two examples are presented. TARPARE is a useful and flexible model for understanding the various segments in a population of interest and for assessing the potential viability of interventions directed at each segment. The model is particularly useful when there is a need to prioritise segments in terms of available budgets. The model provides a disciplined approach to target selection and forces consideration of what weights should be applied to the different criteria, and how these might vary for different issues or for different objectives. TARPARE also assesses segments in terms of an overall likelihood of optimal impact for each segment. Targeting high scoring segments is likely to lead to greater program success than targeting low scoring segments.

  9. BCG vaccination induces HIV target cell activation in HIV-exposed infants in a randomized trial.

    Science.gov (United States)

    Gasper, Melanie A; Hesseling, Anneke C; Mohar, Isaac; Myer, Landon; Azenkot, Tali; Passmore, Jo-Ann S; Hanekom, Willem; Cotton, Mark F; Crispe, I Nicholas; Sodora, Donald L; Jaspan, Heather B

    2017-04-06

    BACKGROUND. Bacillus Calmette-Guérin (BCG) vaccine is administered at birth to protect infants against tuberculosis throughout Africa, where most perinatal HIV-1 transmission occurs. We examined whether BCG vaccination alters the levels of activated HIV target T cells in HIV-exposed South African infants. METHODS. HIV-exposed infants were randomized to receive routine (at birth) or delayed (at 8 weeks) BCG vaccination. Activated and CCR5-expressing peripheral blood CD4+ T cell, monocyte, and NK cell frequencies were evaluated by flow cytometry and immune gene expression via PCR using Biomark (Fluidigm). RESULTS. Of 149 infants randomized, 92% (n = 137) were retained at 6 weeks: 71 in the routine BCG arm and 66 in the delayed arm. Routine BCG vaccination led to a 3-fold increase in systemic activation of HIV target CD4+CCR5+ T cells (HLA-DR+CD38+) at 6 weeks (0.25% at birth versus 0.08% in delayed vaccination groups; P = 0.029), which persisted until 8 weeks of age when the delayed arm was vaccinated. Vaccination of the infants in the delayed arm at 8 weeks resulted in a similar increase in activated CD4+CCR5+ T cells. The increase in activated T cells was associated with increased levels of MHC class II transactivator (CIITA), IL12RB1, and IFN-α1 transcripts within peripheral blood mononuclear cells but minimal changes in innate cells. CONCLUSION. BCG vaccination induces immune changes in HIV-exposed infants, including an increase in the proportion of activated CCR5+CD4+ HIV target cells. These findings provide insight into optimal BCG vaccine timing to minimize the risks of HIV transmissions to exposed infants while preserving potential benefits conferred by BCG vaccination. TRIAL REGISTRATION. ClinicalTrials.gov NCT02062580. FUNDING. This trial was sponsored by the Elizabeth Glaser Pediatric AIDS Foundation (MV-00-9-900-01871-0-00) and the Thrasher Foundation (NR-0095); for details, see Acknowledgments.

  10. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder.

    Science.gov (United States)

    Ellis, Ronald J; Letendre, Scott; Vaida, Florin; Haubrich, Richard; Heaton, Robert K; Sacktor, Ned; Clifford, David B; Best, Brookie M; May, Susanne; Umlauf, Anya; Cherner, Mariana; Sanders, Chelsea; Ballard, Craig; Simpson, David M; Jay, Cheryl; McCutchan, J Allen

    2014-04-01

    Antiretroviral (ARV) medications differentially penetrate across the blood-brain barrier into central nervous system (CNS) tissues, potentially influencing their effectiveness in treating brain infection. This randomized controlled clinical trial (RCT) called for 120 participants at 5 study sites to be randomized 1:1 to CNS-targeted (CNS-T) or non-CNS-T ART. Entry clinical factors such as ARV experience were balanced across arms using an adaptive randomization approach. The primary outcome, change in neurocognitive performance, was measured as the difference in global deficit score (GDS) from baseline to week 16. The study was terminated early on the recommendation of its data safety monitoring board on the basis of slow accrual and a low likelihood of detecting a difference in the primary outcome. No safety concerns were identified. Of 326 participants screened, 59 met entry criteria and were randomized. The primary intent-to-treat analysis included 49 participants who completed week 16. These comprised 39 men and 10 women with a mean age of 44 years (SD, 10 years), and median nadir and current CD4(+) T-cell counts of 175 cells/µL and 242 cells/µL, respectively. The proportional improvement in GDS from baseline was nonsignificantly larger (7%; 95% confidence interval [CI], -31% to 62%) in the CNS-T arm than in the non-CNS-T arm, representing a treatment effect size of 0.09 (95% CI, -.48 to .65). Prespecified secondary analysis showed a trend interaction (P = .087), indicating that participants who had baseline plasma virologic suppression may have benefited from CNS-T. This study found no evidence of neurocognitive benefit for a CNS-T strategy in HIV-associated neurocognitive disorders. A benefit for a subgroup or small overall benefits could not be excluded. Clinical Trials Registration NCT00624195.

  11. Two-year Randomized Clinical Trial Of Self-etching Adhesives And Selective Enamel Etching

    OpenAIRE

    Pena, MR; Rodrigues CE; JA; Ely; Giannini, C.; Reis, M; AF

    2016-01-01

    Objective: The aim of this randomized, controlled prospective clinical trial was to evaluate the clinical effectiveness of restoring noncarious cervical lesions with two self-etching adhesive systems applied with or without selective enamel etching. Methods: A one-step self-etching adhesive (Xeno V+) and a two-step self-etching system (Clearfil SE Bond) were used. The effectiveness of phosphoric acid selective etching of enamel margins was also evaluated. Fifty-six cavities were restored with...

  12. Recursive Random Lasso (RRLasso for Identifying Anti-Cancer Drug Targets.

    Directory of Open Access Journals (Sweden)

    Heewon Park

    Full Text Available Uncovering driver genes is crucial for understanding heterogeneity in cancer. L1-type regularization approaches have been widely used for uncovering cancer driver genes based on genome-scale data. Although the existing methods have been widely applied in the field of bioinformatics, they possess several drawbacks: subset size limitations, erroneous estimation results, multicollinearity, and heavy time consumption. We introduce a novel statistical strategy, called a Recursive Random Lasso (RRLasso, for high dimensional genomic data analysis and investigation of driver genes. For time-effective analysis, we consider a recursive bootstrap procedure in line with the random lasso. Furthermore, we introduce a parametric statistical test for driver gene selection based on bootstrap regression modeling results. The proposed RRLasso is not only rapid but performs well for high dimensional genomic data analysis. Monte Carlo simulations and analysis of the "Sanger Genomics of Drug Sensitivity in Cancer dataset from the Cancer Genome Project" show that the proposed RRLasso is an effective tool for high dimensional genomic data analysis. The proposed methods provide reliable and biologically relevant results for cancer driver gene selection.

  13. Near surface swimming of Salmonella Typhimurium explains target-site selection and cooperative invasion.

    Directory of Open Access Journals (Sweden)

    Benjamin Misselwitz

    Full Text Available Targeting of permissive entry sites is crucial for bacterial infection. The targeting mechanisms are incompletely understood. We have analyzed target-site selection by S. Typhimurium. This enteropathogenic bacterium employs adhesins (e.g. fim and the type III secretion system 1 (TTSS-1 for host cell binding, the triggering of ruffles and invasion. Typically, S. Typhimurium invasion is focused on a subset of cells and multiple bacteria invade via the same ruffle. It has remained unclear how this is achieved. We have studied target-site selection in tissue culture by time lapse microscopy, movement pattern analysis and modeling. Flagellar motility (but not chemotaxis was required for reaching the host cell surface in vitro. Subsequently, physical forces trapped the pathogen for ∼1.5-3 s in "near surface swimming". This increased the local pathogen density and facilitated "scanning" of the host surface topology. We observed transient TTSS-1 and fim-independent "stopping" and irreversible TTSS-1-mediated docking, in particular at sites of prominent topology, i.e. the base of rounded-up cells and membrane ruffles. Our data indicate that target site selection and the cooperative infection of membrane ruffles are attributable to near surface swimming. This mechanism might be of general importance for understanding infection by flagellated bacteria.

  14. Modelling the consequences of targeted selective treatment strategies on performance and emergence of anthelmintic resistance amongst grazing calves

    Directory of Open Access Journals (Sweden)

    Zoe Berk

    2016-12-01

    Full Text Available The development of anthelmintic resistance by helminths can be slowed by maintaining refugia on pasture or in untreated hosts. Targeted selective treatments (TST may achieve this through the treatment only of individuals that would benefit most from anthelmintic, according to certain criteria. However TST consequences on cattle are uncertain, mainly due to difficulties of comparison between alternative strategies. We developed a mathematical model to compare: 1 the most ‘beneficial’ indicator for treatment selection and 2 the method of selection of calves exposed to Ostertagia ostertagi, i.e. treating a fixed percentage of the population with the lowest (or highest indicator values versus treating individuals who exceed (or are below a given indicator threshold. The indicators evaluated were average daily gain (ADG, faecal egg counts (FEC, plasma pepsinogen, combined FEC and plasma pepsinogen, versus random selection of individuals. Treatment success was assessed in terms of benefit per R (BPR, the ratio of average benefit in weight gain to change in frequency of resistance alleles R (relative to an untreated population. The optimal indicator in terms of BPR for fixed percentages of calves treated was plasma pepsinogen and the worst ADG; in the latter case treatment was applied to some individuals who were not in need of treatment. The reverse was found when calves were treated according to threshold criteria, with ADG being the best target indicator for treatment. This was also the most beneficial strategy overall, with a significantly higher BPR value than any other strategy, but its degree of success depended on the chosen threshold of the indicator. The study shows strong support for TST, with all strategies showing improvements on calves treated selectively, compared with whole-herd treatment at 3, 8, 13 weeks post-turnout. The developed model appeared capable of assessing the consequences of other TST strategies on calf populations.

  15. Competition between color and luminance for target selection in smooth pursuit and saccadic eye movements.

    Science.gov (United States)

    Spering, Miriam; Montagnini, Anna; Gegenfurtner, Karl R

    2008-11-24

    Visual processing of color and luminance for smooth pursuit and saccadic eye movements was investigated using a target selection paradigm. In two experiments, stimuli were varied along the dimensions color and luminance, and selection of the more salient target was compared in pursuit and saccades. Initial pursuit was biased in the direction of the luminance component whereas saccades showed a relative preference for color. An early pursuit response toward luminance was often reversed to color by a later saccade. Observers' perceptual judgments of stimulus salience, obtained in two control experiments, were clearly biased toward luminance. This choice bias in perceptual data implies that the initial short-latency pursuit response agrees with perceptual judgments. In contrast, saccades, which have a longer latency than pursuit, do not seem to follow the perceptual judgment of salience but instead show a stronger relative preference for color. These substantial differences in target selection imply that target selection processes for pursuit and saccadic eye movements use distinctly different weights for color and luminance stimuli.

  16. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  17. Joint Effect of Insertion of Spaces and Word Length in Saccade Target Selection in Chinese Reading

    Science.gov (United States)

    Li, Xingshan; Shen, Wei

    2013-01-01

    The present study examined how insertion of spaces before and after a word affects saccade target selection in Chinese reading. We found that inserting spaces in Chinese text changes the eye movement behaviour of Chinese readers. They are less likely to fixate on the character near the space and will try their best to process the entire word with…

  18. Hebbian Learning in a Random Network Captures Selectivity Properties of the Prefrontal Cortex.

    Science.gov (United States)

    Lindsay, Grace W; Rigotti, Mattia; Warden, Melissa R; Miller, Earl K; Fusi, Stefano

    2017-11-08

    Complex cognitive behaviors, such as context-switching and rule-following, are thought to be supported by the prefrontal cortex (PFC). Neural activity in the PFC must thus be specialized to specific tasks while retaining flexibility. Nonlinear "mixed" selectivity is an important neurophysiological trait for enabling complex and context-dependent behaviors. Here we investigate (1) the extent to which the PFC exhibits computationally relevant properties, such as mixed selectivity, and (2) how such properties could arise via circuit mechanisms. We show that PFC cells recorded from male and female rhesus macaques during a complex task show a moderate level of specialization and structure that is not replicated by a model wherein cells receive random feedforward inputs. While random connectivity can be effective at generating mixed selectivity, the data show significantly more mixed selectivity than predicted by a model with otherwise matched parameters. A simple Hebbian learning rule applied to the random connectivity, however, increases mixed selectivity and enables the model to match the data more accurately. To explain how learning achieves this, we provide analysis along with a clear geometric interpretation of the impact of learning on selectivity. After learning, the model also matches the data on measures of noise, response density, clustering, and the distribution of selectivities. Of two styles of Hebbian learning tested, the simpler and more biologically plausible option better matches the data. These modeling results provide clues about how neural properties important for cognition can arise in a circuit and make clear experimental predictions regarding how various measures of selectivity would evolve during animal training. SIGNIFICANCE STATEMENT The prefrontal cortex is a brain region believed to support the ability of animals to engage in complex behavior. How neurons in this area respond to stimuli-and in particular, to combinations of stimuli ("mixed

  19. Selecting Optimal Parameters of Random Linear Network Coding for Wireless Sensor Networks

    DEFF Research Database (Denmark)

    Heide, Janus; Zhang, Qi; Fitzek, Frank

    2013-01-01

    This work studies how to select optimal code parameters of Random Linear Network Coding (RLNC) in Wireless Sensor Networks (WSNs). With Rateless Deluge [1] the authors proposed to apply Network Coding (NC) for Over-the-Air Programming (OAP) in WSNs, and demonstrated that with NC a significant...

  20. Integrated Approach to Construction of Benchmarking Network in DEA-Based Stepwise Benchmark Target Selection

    Directory of Open Access Journals (Sweden)

    Jaehun Park

    2016-06-01

    Full Text Available Stepwise benchmark target selection in data envelopment analysis (DEA is a realistic and effective method by which inefficient decision-making units (DMUs can choose benchmarks in a stepwise manner. We propose, for the construction of a benchmarking network (i.e., a network structure consisting of an alternative sequence of benchmark targets, an approach that integrates the cross-efficiency DEA, K-means clustering and context-dependent DEA methods to minimize resource improvement pattern inconsistency in the selection of the intermediate benchmark targets (IBTs of an inefficient DMU. The specific advantages and overall effectiveness of the proposed method were demonstrated by application to a case study of 34 actual container terminal ports and the successful determination of the stepwise benchmarking path of an inefficient DMU.

  1. Patient selection and targeted treatment in the management of platinum-resistant ovarian cancer

    Directory of Open Access Journals (Sweden)

    Leamon PC

    2013-09-01

    Full Text Available Christopher P Leamon,1 Chandra D Lovejoy,2 Binh Nguyen3 1Research and Development, 2Regulatory Affairs, 3Clinical Affairs, Endocyte Inc, West Lafayette, IN, USA Abstract: Ovarian cancer (OC has the highest mortality rate of any gynecologic cancer, and patients generally have a poor prognosis due to high chemotherapy resistance and late stage disease diagnosis. Platinum-resistant OC can be treated with cytotoxic chemotherapy such as paclitaxel, topotecan, pegylated liposomal doxorubicin, and gemcitabine, but many patients eventually relapse upon treatment. Fortunately, there are currently a number of targeted therapies in development for these patients who have shown promising results in recent clinical trials. These treatments often target the vascular endothelial growth factor pathway (eg, bevacizumab and aflibercept, DNA repair mechanisms (eg, iniparib and olaparib, or they are directed against folate related pathways (eg, pemetrexed, farletuzumab, and vintafolide. As many targeted therapies are only effective in a subset of patients, there is an increasing need for the identification of response predictive biomarkers. Selecting the right patients through biomarker screening will help tailor therapy to patients and decrease superfluous treatment to those who are biomarker negative; this approach should lead to improved clinical results and decreased toxicities. In this review the current targeted therapies used for treating platinum-resistant OC are discussed. Furthermore, use of prognostic and response predictive biomarkers to define OC patient populations that may benefit from specific targeted therapies is also highlighted. Keywords: platinum-resistant ovarian cancer, targeted therapy, patient selection, folate receptor, VEGF, biomarkers

  2. Improving target amino acid selectivity in a permissive aminoacyl tRNA synthetase through counter-selection.

    Science.gov (United States)

    Sungwienwong, Itthipol; Hostetler, Zachary M; Blizzard, Robert J; Porter, Joseph J; Driggers, Camden M; Mbengi, Lea Z; Villegas, José A; Speight, Lee C; Saven, Jeffery G; Perona, John J; Kohli, Rahul M; Mehl, Ryan A; Petersson, E James

    2017-05-03

    The amino acid acridon-2-ylalanine (Acd) can be a valuable probe of protein dynamics, either alone or as part of a Förster resonance energy transfer (FRET) or photo-induced electron transfer (eT) probe pair. We have previously reported the genetic incorporation of Acd by an aminoacyl tRNA synthetase (RS). However, this RS, developed from a library of permissive RSs, also incorporates N-phenyl-aminophenylalanine (Npf), a trace byproduct of one Acd synthetic route. We have performed negative selections in the presence of Npf and analyzed the selectivity of the resulting AcdRSs by in vivo protein expression and detailed kinetic analyses of the purified RSs. We find that selection conferred a ∼50-fold increase in selectivity for Acd over Npf, eliminating incorporation of Npf contaminants, and allowing one to use a high yielding Acd synthetic route for improved overall expression of Acd-containing proteins. More generally, our report also provides a cautionary tale on the use of permissive RSs, as well as a strategy for improving selectivity for the target amino acid.

  3. Target-distractor synchrony affects performance in a novel motor task for studying action selection

    Science.gov (United States)

    Paine, Phillip J.; Heaton, Timothy J.; Anderson, Sean; Da Lio, Mauro; Gurney, Kevin

    2017-01-01

    The study of action selection in humans can present challenges of task design since our actions are usually defined by many degrees of freedom and therefore occupy a large action-space. While saccadic eye-movement offers a more constrained paradigm for investigating action selection, the study of reach-and-grasp in upper limbs has often been defined by more complex scenarios, not easily interpretable in terms of such selection. Here we present a novel motor behaviour task which addresses this by limiting the action space to a single degree of freedom in which subjects have to track (using a stylus) a vertical coloured target line displayed on a tablet computer, whilst ignoring a similarly oriented distractor line in a different colour. We ran this task with 55 subjects and showed that, in agreement with previous studies, the presence of the distractor generally increases the movement latency and directional error rate. Further, we used two distractor conditions according to whether the distractor’s location changes asynchronously or synchronously with the location of the target. We found that the asynchronous distractor yielded poorer performance than its synchronous counterpart, with significantly higher movement latencies and higher error rates. We interpret these results in an action selection framework with two actions (move left or right) and competing ‘action requests’ offered by the target and distractor. As such, the results provide insights into action selection performance in humans and supply data for directly constraining future computational models therein. PMID:28475622

  4. Accuracy of geographically targeted internet advertisements on Google AdWords for recruitment in a randomized trial.

    Science.gov (United States)

    Jones, Ray B; Goldsmith, Lesley; Williams, Christopher J; Kamel Boulos, Maged N

    2012-06-20

    Google AdWords are increasingly used to recruit people into research studies and clinical services. They offer the potential to recruit from targeted control areas in cluster randomized controlled trials (RCTs), but little is known about the feasibility of accurately targeting ads by location and comparing with control areas. To examine the accuracy and contamination of control areas by a location-targeted online intervention using Google AdWords in a pilot cluster RCT. Based on previous use of online cognitive behavioral therapy for depression and population size, we purposively selected 16 of the 121 British postcode areas and randomized them to three intervention and one (do-nothing) control arms. Two intervention arms included use of location-targeted AdWords, and we compared these with the do-nothing control arm. We did not raise the visibility of our research website to normal Web searches. Users who clicked on the ad were directed to our project website, which collected the computer Internet protocol (IP) address, date, and time. Visitors were asked for their postcode area and to complete the Patient Health Questionnaire (depression). They were then offered links to several online depression resources. Google Analytics largely uses IP methods to estimate location, but AdWords uses additional information. We compared locations assessed by (1) Analytics, and (2) as self-identified by users. Ads were shown 300,523 times with 4207 click-throughs. There were few site visits except through AdWord click-throughs. Both methods of location assessment agreed there was little contamination of control areas. According to Analytics, 69.75% (2617/3752) of participants were in intervention areas, only 0% (8/3752) in control areas, but 30.04% (1127/3752) in other areas. However, according to user-stated postcodes, only 20.7% (463/2237) were in intervention areas, 1% (22/2236) in control areas, but 78.31% (1751/2236) in other areas. Both location assessments suggested most

  5. $k$-core percolation on complex networks: Comparing random, localized and targeted attacks

    CERN Document Server

    Yuan, Xin; Stanley, H Eugene; Havlin, Shlomo

    2016-01-01

    The type of malicious attack inflicting on networks greatly influences their stability under ordinary percolation in which a node fails when it becomes disconnected from the giant component. Here we study its generalization, $k$-core percolation, in which a node fails when it loses connection to a threshold $k$ number of neighbors. We study and compare analytically and by numerical simulations of $k$-core percolation the stability of networks under random attacks (RA), localized attacks (LA) and targeted attacks (TA), respectively. By mapping a network under LA or TA into an equivalent network under RA, we find that in both single and interdependent networks, TA exerts the greatest damage to the core structure of a network. We also find that for Erd\\H{o}s-R\\'{e}nyi (ER) networks, LA and RA exert equal damage to the core structure whereas for scale-free (SF) networks, LA exerts much more damage than RA does to the core structure.

  6. Tehran Air Pollutants Prediction Based on Random Forest Feature Selection Method

    Science.gov (United States)

    Shamsoddini, A.; Aboodi, M. R.; Karami, J.

    2017-09-01

    Air pollution as one of the most serious forms of environmental pollutions poses huge threat to human life. Air pollution leads to environmental instability, and has harmful and undesirable effects on the environment. Modern prediction methods of the pollutant concentration are able to improve decision making and provide appropriate solutions. This study examines the performance of the Random Forest feature selection in combination with multiple-linear regression and Multilayer Perceptron Artificial Neural Networks methods, in order to achieve an efficient model to estimate carbon monoxide and nitrogen dioxide, sulfur dioxide and PM2.5 contents in the air. The results indicated that Artificial Neural Networks fed by the attributes selected by Random Forest feature selection method performed more accurate than other models for the modeling of all pollutants. The estimation accuracy of sulfur dioxide emissions was lower than the other air contaminants whereas the nitrogen dioxide was predicted more accurate than the other pollutants.

  7. TEHRAN AIR POLLUTANTS PREDICTION BASED ON RANDOM FOREST FEATURE SELECTION METHOD

    Directory of Open Access Journals (Sweden)

    A. Shamsoddini

    2017-09-01

    Full Text Available Air pollution as one of the most serious forms of environmental pollutions poses huge threat to human life. Air pollution leads to environmental instability, and has harmful and undesirable effects on the environment. Modern prediction methods of the pollutant concentration are able to improve decision making and provide appropriate solutions. This study examines the performance of the Random Forest feature selection in combination with multiple-linear regression and Multilayer Perceptron Artificial Neural Networks methods, in order to achieve an efficient model to estimate carbon monoxide and nitrogen dioxide, sulfur dioxide and PM2.5 contents in the air. The results indicated that Artificial Neural Networks fed by the attributes selected by Random Forest feature selection method performed more accurate than other models for the modeling of all pollutants. The estimation accuracy of sulfur dioxide emissions was lower than the other air contaminants whereas the nitrogen dioxide was predicted more accurate than the other pollutants.

  8. Can Targeted Intervention Mitigate Early Emotional and Behavioral Problems?: Generating Robust Evidence within Randomized Controlled Trials.

    Directory of Open Access Journals (Sweden)

    Orla Doyle

    Full Text Available This study examined the impact of a targeted Irish early intervention program on children's emotional and behavioral development using multiple methods to test the robustness of the results. Data on 164 Preparing for Life participants who were randomly assigned into an intervention group, involving home visits from pregnancy onwards, or a control group, was used to test the impact of the intervention on Child Behavior Checklist scores at 24-months. Using inverse probability weighting to account for differential attrition, permutation testing to address small sample size, and quantile regression to characterize the distributional impact of the intervention, we found that the few treatment effects were largely concentrated among boys most at risk of developing emotional and behavioral problems. The average treatment effect identified a 13% reduction in the likelihood of falling into the borderline clinical threshold for Total Problems. The interaction and subgroup analysis found that this main effect was driven by boys. The distributional analysis identified a 10-point reduction in the Externalizing Problems score for boys at the 90th percentile. No effects were observed for girls or for the continuous measures of Total, Internalizing, and Externalizing problems. These findings suggest that the impact of this prenatally commencing home visiting program may be limited to boys experiencing the most difficulties. Further adoption of the statistical methods applied here may help to improve the internal validity of randomized controlled trials and contribute to the field of evaluation science more generally.ISRCTN Registry ISRCTN04631728.

  9. Long-term memories bias sensitivity and target selection in complex scenes.

    Science.gov (United States)

    Patai, Eva Zita; Doallo, Sonia; Nobre, Anna Christina

    2012-12-01

    In everyday situations, we often rely on our memories to find what we are looking for in our cluttered environment. Recently, we developed a new experimental paradigm to investigate how long-term memory (LTM) can guide attention and showed how the pre-exposure to a complex scene in which a target location had been learned facilitated the detection of the transient appearance of the target at the remembered location [Summerfield, J. J., Rao, A., Garside, N., & Nobre, A. C. Biasing perception by spatial long-term memory. The Journal of Neuroscience, 31, 14952-14960, 2011; Summerfield, J. J., Lepsien, J., Gitelman, D. R., Mesulam, M. M., & Nobre, A. C. Orienting attention based on long-term memory experience. Neuron, 49, 905-916, 2006]. This study extends these findings by investigating whether and how LTM can enhance perceptual sensitivity to identify targets occurring within their complex scene context. Behavioral measures showed superior perceptual sensitivity (d') for targets located in remembered spatial contexts. We used the N2pc ERP to test whether LTM modulated the process of selecting the target from its scene context. Surprisingly, in contrast to effects of visual spatial cues or implicit contextual cueing, LTM for target locations significantly attenuated the N2pc potential. We propose that the mechanism by which these explicitly available LTMs facilitate perceptual identification of targets may differ from mechanisms triggered by other types of top-down sources of information.

  10. Extreme selective sweeps independently targeted the X chromosomes of the great apes.

    Science.gov (United States)

    Nam, Kiwoong; Munch, Kasper; Hobolth, Asger; Dutheil, Julien Yann; Veeramah, Krishna R; Woerner, August E; Hammer, Michael F; Mailund, Thomas; Schierup, Mikkel Heide

    2015-05-19

    The unique inheritance pattern of the X chromosome exposes it to natural selection in a way that is different from that of the autosomes, potentially resulting in accelerated evolution. We perform a comparative analysis of X chromosome polymorphism in 10 great ape species, including humans. In most species, we identify striking megabase-wide regions, where nucleotide diversity is less than 20% of the chromosomal average. Such regions are found exclusively on the X chromosome. The regions overlap partially among species, suggesting that the underlying targets are partly shared among species. The regions have higher proportions of singleton SNPs, higher levels of population differentiation, and a higher nonsynonymous-to-synonymous substitution ratio than the rest of the X chromosome. We show that the extent to which diversity is reduced is incompatible with direct selection or the action of background selection and soft selective sweeps alone, and therefore, we suggest that very strong selective sweeps have independently targeted these specific regions in several species. The only genomic feature that we can identify as strongly associated with loss of diversity is the location of testis-expressed ampliconic genes, which also have reduced diversity around them. We hypothesize that these genes may be responsible for selective sweeps in the form of meiotic drive caused by an intragenomic conflict in male meiosis.

  11. Classification of epileptic EEG signals based on simple random sampling and sequential feature selection.

    Science.gov (United States)

    Ghayab, Hadi Ratham Al; Li, Yan; Abdulla, Shahab; Diykh, Mohammed; Wan, Xiangkui

    2016-06-01

    Electroencephalogram (EEG) signals are used broadly in the medical fields. The main applications of EEG signals are the diagnosis and treatment of diseases such as epilepsy, Alzheimer, sleep problems and so on. This paper presents a new method which extracts and selects features from multi-channel EEG signals. This research focuses on three main points. Firstly, simple random sampling (SRS) technique is used to extract features from the time domain of EEG signals. Secondly, the sequential feature selection (SFS) algorithm is applied to select the key features and to reduce the dimensionality of the data. Finally, the selected features are forwarded to a least square support vector machine (LS_SVM) classifier to classify the EEG signals. The LS_SVM classifier classified the features which are extracted and selected from the SRS and the SFS. The experimental results show that the method achieves 99.90, 99.80 and 100 % for classification accuracy, sensitivity and specificity, respectively.

  12. In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A

    Science.gov (United States)

    Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

    2015-01-01

    A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5’-end including the 5’-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer. PMID:26221730

  13. Aromatic Functionality of Target Proteins Influences Monomer Selection for Creating Artificial Antibodies on Plasmonic Biosensors.

    Science.gov (United States)

    Hu, Rong; Luan, Jingyi; Kharasch, Evan D; Singamaneni, Srikanth; Morrissey, Jeremiah J

    2017-01-11

    Natural antibodies used as biorecognition elements suffer from numerous shortcomings, such as limited chemical and environmental stability and cost. Artificial antibodies based on molecular imprinting are an attractive alternative to natural antibodies. We investigated the role of aromatic interactions in target recognition capabilities of artificial antibodies. Three proteins with different aromatic amino acid content were employed as model targets. Artificial antibodies were formed on nanostructures using combinations of silane monomers of varying aromatic functionality. We employed refractive index sensitivity of plasmonic nanostructures as a transduction platform for monitoring various steps in the imprinting process and to quantify the target recognition capabilities of the artificial antibodies. The sensitivity of the artificial antibodies with aromatic interactions exhibited a protein-dependent enhancement. Selectivity and sensitivity enhancement due to the presence of aromatic groups in imprinted polymer matrix was found to be higher for target proteins with higher aromatic amino acid content. Our results indicate that tailoring the monomer composition based on the amino acid content of the target protein can improve the sensitivity of plasmonic biosensors based on artificial antibodies without affecting the selectivity.

  14. Out with the old? The role of selective attention in retaining targets in partial report.

    Science.gov (United States)

    Lindsey, Dakota R B; Bundesen, Claus; Kyllingsbæk, Søren; Petersen, Anders; Logan, Gordon D

    2017-01-01

    In the partial-report task, subjects are asked to report only a portion of the items presented. Selective attention chooses which objects to represent in short-term memory (STM) on the basis of their relevance. Because STM is limited in capacity, one must sometimes choose which objects are removed from memory in light of new relevant information. We tested the hypothesis that the choices among newly presented information and old information in STM involve the same process-that both are acts of selective attention. We tested this hypothesis using a two-display partial-report procedure. In this procedure, subjects had to select and retain relevant letters (targets) from two sequentially presented displays. If selection in perception and retention in STM are the same process, then irrelevant letters (distractors) in the second display, which demanded attention because of their similarity to the targets, should have decreased target report from the first display. This effect was not obtained in any of four experiments. Thus, choosing objects to keep in STM is not the same process as choosing new objects to bring into STM.

  15. Prehospital cooling to improve successful targeted temperature management after cardiac arrest: A randomized controlled trial.

    Science.gov (United States)

    Scales, D C; Cheskes, S; Verbeek, P R; Pinto, R; Austin, D; Brooks, S C; Dainty, K N; Goncharenko, K; Mamdani, M; Thorpe, K E; Morrison, L J

    2017-10-05

    Targeted temperature management (TTM) improves survival with good neurological outcome after out-of-hospital cardiac arrest (OHCA), but is delivered inconsistently and often with delay. To determine if prehospital cooling by paramedics leads to higher rates of 'successful TTM', defined as achieving a target temperature of 32-34°C within 6h of hospital arrival. Pragmatic RCT comparing prehospital cooling (surface ice packs, cold saline infusion, wristband reminders) initiated 5min after return of spontaneous circulation (ROSC) versus usual resuscitation and transport. The primary outcome was rate of 'successful TTM'; secondary outcomes were rates of applying TTM in hospital, survival with good neurological outcome, pulmonary edema in emergency department, and re-arrest during transport. 585 patients were randomized to receive prehospital cooling (n=279) or control (n=306). Prehospital cooling did not increase rates of 'successful TTM' (30% vs 25%; RR, 1.17; 95% confidence interval [CI] 0.91-1.52; p=0.22), but increased rates of applying TTM in hospital (68% vs 56%; RR, 1.21; 95%CI 1.07-1.37; p=0.003). Survival with good neurological outcome (29% vs 26%; RR, 1.13, 95%CI 0.87-1.47; p=0.37) was similar. Prehospital cooling was not associated with re-arrest during transport (7.5% vs 8.2%; RR, 0.94; 95%CI 0.54-1.63; p=0.83) but was associated with decreased incidence of pulmonary edema in emergency department (12% vs 18%; RR, 0.66; 95%CI 0.44-0.99; p=0.04). Prehospital cooling initiated 5min after ROSC did not increase rates of achieving a target temperature of 32-34°C within 6h of hospital arrival but was safe and increased application of TTM in hospital. Copyright © 2017. Published by Elsevier B.V.

  16. Identifying co-targets to fight drug resistance based on a random walk model

    Directory of Open Access Journals (Sweden)

    Chen Liang-Chun

    2012-01-01

    Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.

  17. Personal name in Igbo Culture: A dataset on randomly selected personal names and their statistical analysis.

    Science.gov (United States)

    Okagbue, Hilary I; Opanuga, Abiodun A; Adamu, Muminu O; Ugwoke, Paulinus O; Obasi, Emmanuela C M; Eze, Grace A

    2017-12-01

    This data article contains the statistical analysis of Igbo personal names and a sample of randomly selected of such names. This was presented as the following: 1). A simple random sampling of some Igbo personal names and their respective gender associated with each name. 2). The distribution of the vowels, consonants and letters of alphabets of the personal names. 3). The distribution of name length. 4). The distribution of initial and terminal letters of Igbo personal names. The significance of the data was discussed.

  18. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    DEFF Research Database (Denmark)

    Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P

    2017-01-01

    , selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage...... also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent...... model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases....

  19. Specific and selective target detection of supra-genome 21 Mers Salmonella via silicon nanowires biosensor

    Science.gov (United States)

    Mustafa, Mohammad Razif Bin; Dhahi, Th S.; Ehfaed, Nuri. A. K. H.; Adam, Tijjani; Hashim, U.; Azizah, N.; Mohammed, Mohammed; Noriman, N. Z.

    2017-09-01

    The nano structure based on silicon can be surface modified to be used as label-free biosensors that allow real-time measurements. The silicon nanowire surface was functionalized using 3-aminopropyltrimethoxysilane (APTES), which functions as a facilitator to immobilize biomolecules on the silicon nanowire surface. The process is simple, economical; this will pave the way for point-of-care applications. However, the surface modification and subsequent detection mechanism still not clear. Thus, study proposed step by step process of silicon nano surface modification and its possible in specific and selective target detection of Supra-genome 21 Mers Salmonella. The device captured the molecule with precisely; the approach took the advantages of strong binding chemistry created between APTES and biomolecule. The results indicated how modifications of the nanowires provide sensing capability with strong surface chemistries that can lead to specific and selective target detection.

  20. Photostick: a method for selective isolation of target cells from culture.

    Science.gov (United States)

    Chien, Miao-Ping; Werley, Christopher A; Farhi, Samouil L; Cohen, Adam E

    2015-03-01

    Sorting of target cells from a heterogeneous pool is technically difficult when the selection criterion is complex, e.g. a dynamic response, a morphological feature, or a combination of multiple parameters. At present, mammalian cell selections are typically performed either via static fluorescence (e.g. fluorescence activated cell sorter), via survival (e.g. antibiotic resistance), or via serial operations (flow cytometry, laser capture microdissection). Here we present a simple protocol for selecting cells based on any static or dynamic property that can be identified by video microscopy and image processing. The "photostick" technique uses a cell-impermeant photochemical crosslinker and digital micromirror array-based patterned illumination to immobilize selected cells on the culture dish. Other cells are washed away with mild protease treatment. The crosslinker also labels the selected cells with a fluorescent dye and a biotin for later identification. The photostick protocol preserves cell viability, permits genetic profiling of selected cells, and can be performed with complex functional selection criteria such as neuronal firing patterns.

  1. Metaproteomics-guided selection of targeted enzymes for bioprospecting of mixed microbial communities

    OpenAIRE

    Speda, Jutta; Jonsson, Bengt-Harald; Carlsson, Uno; Karlsson, Martin

    2017-01-01

    Background: Hitherto, the main goal of metaproteomic analyses has been to characterize the functional role of particular microorganisms in the microbial ecology of various microbial communities. Recently, it has been suggested that metaproteomics could be used for bioprospecting microbial communities to query for the most active enzymes to improve the selection process of industrially relevant enzymes. In the present study, to reduce the complexity of metaproteomic samples for targeted biopro...

  2. Microfluidics for Drug Discovery and Development: From Target Selection to Product Lifecycle Management

    Science.gov (United States)

    Kang, Lifeng; Chung, Bong Geun; Langer, Robert; Khademhosseini, Ali

    2009-01-01

    Microfluidic technologies’ ability to miniaturize assays and increase experimental throughput have generated significant interest in the drug discovery and development domain. These characteristics make microfluidic systems a potentially valuable tool for many drug discovery and development applications. Here, we review the recent advances of microfluidic devices for drug discovery and development and highlight their applications in different stages of the process, including target selection, lead identification, preclinical tests, clinical trials, chemical synthesis, formulations studies, and product management. PMID:18190858

  3. Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation

    Directory of Open Access Journals (Sweden)

    Sven Kruspe

    2014-01-01

    Full Text Available Photodynamic therapy (PDT uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6 with a human interleukin-6 receptor (IL-6R binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R+ cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.

  4. Retroviral DNA integration: viral and cellular determinants of target-site selection.

    Directory of Open Access Journals (Sweden)

    Mary K Lewinski

    2006-06-01

    Full Text Available Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV integrates preferentially within active transcription units, whereas murine leukemia virus (MLV integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN coding region into HIV (to make HIVmIN caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I-hypersensitive sites (i.e., +/- 1 kb, and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.

  5. Merger and Acquisition Target Selection Based on Interval Neutrosophic Multigranulation Rough Sets over Two Universes

    Directory of Open Access Journals (Sweden)

    Chao Zhang

    2017-07-01

    Full Text Available As a significant business activity, merger and acquisition (M&A generally means transactions in which the ownership of companies, other business organizations or their operating units are transferred or combined. In a typical M&A procedure, M&A target selection is an important issue that tends to exert an increasingly significant impact on different business areas. Although some research works based on fuzzy methods have been explored on this issue, they can only deal with incomplete and uncertain information, but not inconsistent and indeterminate information that exists universally in the decision making process. Additionally, it is advantageous to solve M&A problems under the group decision making context. In order to handle these difficulties in M&A target selection background, we introduce a novel rough set model by combining interval neutrosophic sets (INSs with multigranulation rough sets over two universes, called an interval neutrosophic (IN multigranulation rough set over two universes. Then, we discuss the definition and some fundamental properties of the proposed model. Finally, we establish decision making rules and computing approaches for the proposed model in M&A target selection background, and the effectiveness of the decision making approach is demonstrated by an illustrative case analysis.

  6. Fuzzy System-Based Target Selection for a NIR Camera-Based Gaze Tracker

    Science.gov (United States)

    Naqvi, Rizwan Ali; Arsalan, Muhammad; Park, Kang Ryoung

    2017-01-01

    Gaze-based interaction (GBI) techniques have been a popular subject of research in the last few decades. Among other applications, GBI can be used by persons with disabilities to perform everyday tasks, as a game interface, and can play a pivotal role in the human computer interface (HCI) field. While gaze tracking systems have shown high accuracy in GBI, detecting a user’s gaze for target selection is a challenging problem that needs to be considered while using a gaze detection system. Past research has used the blinking of the eyes for this purpose as well as dwell time-based methods, but these techniques are either inconvenient for the user or requires a long time for target selection. Therefore, in this paper, we propose a method for fuzzy system-based target selection for near-infrared (NIR) camera-based gaze trackers. The results of experiments performed in addition to tests of the usability and on-screen keyboard use of the proposed method show that it is better than previous methods. PMID:28420114

  7. Fuzzy System-Based Target Selection for a NIR Camera-Based Gaze Tracker.

    Science.gov (United States)

    Naqvi, Rizwan Ali; Arsalan, Muhammad; Park, Kang Ryoung

    2017-04-14

    Gaze-based interaction (GBI) techniques have been a popular subject of research in the last few decades. Among other applications, GBI can be used by persons with disabilities to perform everyday tasks, as a game interface, and can play a pivotal role in the human computer interface (HCI) field. While gaze tracking systems have shown high accuracy in GBI, detecting a user's gaze for target selection is a challenging problem that needs to be considered while using a gaze detection system. Past research has used the blinking of the eyes for this purpose as well as dwell time-based methods, but these techniques are either inconvenient for the user or requires a long time for target selection. Therefore, in this paper, we propose a method for fuzzy system-based target selection for near-infrared (NIR) camera-based gaze trackers. The results of experiments performed in addition to tests of the usability and on-screen keyboard use of the proposed method show that it is better than previous methods.

  8. BLAST: Battery Lifetime-constrained Adaptation with Selected Target in Mobile Devices

    Directory of Open Access Journals (Sweden)

    Pietro Mercati

    2015-08-01

    Full Text Available Mobile devices today contain many power hungry subsystems and execute different applications. Standard power management is not aware of the desired battery lifetime and has no visibility into which applications are executing. However, power consumption is strongly dependent on which applications are executed. In this work, we propose a novel power characterization strategy for mobile devices called application-dependent power states (AP-states. Based on that, we formulate a management problem to improve performance under battery lifetime constraints, and we implement the management framework on a real Android device. We call our framework BLAST: Battery Lifetime-constrained Adaptation with Selected Target. The goal of such framework is to maximize performance while letting the device battery to last at least for a certain required lifetime, and only requires the user to select the desired target lifetime. The implementation does not require OS modifications and can be ported and installed to any Android device. We experimentally verify that our strategy can still meets user experience requirements with a selected target battery lifetime extension of at least 25%.

  9. DO IT Trial: vitamin D Outcomes and Interventions in Toddlers - a TARGet Kids! randomized controlled trial.

    Science.gov (United States)

    Maguire, Jonathon L; Birken, Catherine S; Loeb, Mark B; Mamdani, Muhammad; Thorpe, Kevin; Hoch, Jeffrey S; Mazzulli, Tony; Borkhoff, Cornelia M; Macarthur, Colin; Parkin, Patricia C

    2014-02-08

    Vitamin D levels are alarmingly low (respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of 'high dose' (2000 IU/day) vs. 'standard dose' (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of 'high dose' vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI. This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1-5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the 'standard dose' or 'high dose' oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups. Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs. This information will assist in determining practice and

  10. The role of target elevation in prey selection by tiger beetles (Carabidae: Cicindela spp.).

    Science.gov (United States)

    Layne, John E; Chen, P W; Gilbert, Cole

    2006-11-01

    The elevation of objects in the visual field has long been recognized as a potential distance cue, but it has been demonstrated to a reasonable extent in only four species: humans, frogs, fiddler crabs and backswimmers. Many tiger beetles hunt in flat, sandy areas, and their eyes show "flat-world" adaptations, such as an extended visual streak of higher acuity that corresponds to the horizon. They are therefore possible candidates for the use of elevation as a cue for distance. We tested this empirically and with simulation. In a behavioral prey selection paradigm, in which starved beetles were presented moving prey-targets having different size, speed and elevation, the beetles showed a strong preference for large targets when these were low in the visual field and a weaker preference for small targets when these were near the horizon. Striking of targets above the horizon was reduced compared to sub-horizontal targets, and lacked the size-elevation interaction. We simulated these empirical results with a model that converted elevation to distance, and used distance to estimate the absolute size of the targets. Simulated strike probability was then determined by the similarity between this absolute size and an independently confirmed preferred prey size. The results of the simulation model matched the empirical data as well as the best statistical model of the behavioral results. While some aspects of the model, and the beetles' behavior, differ from the strict geometry of the "elevation hypothesis", our results nevertheless indicate that tiger beetles use elevation to estimate distance to prey, and that it is therefore one of the determinants of prey selection.

  11. Classification of epileptic EEG signals based on simple random sampling and sequential feature selection

    OpenAIRE

    Ghayab, Hadi Ratham Al; Li, Yan; Abdulla, Shahab; Diykh, Mohammed; Wan, Xiangkui

    2016-01-01

    Electroencephalogram (EEG) signals are used broadly in the medical fields. The main applications of EEG signals are the diagnosis and treatment of diseases such as epilepsy, Alzheimer, sleep problems and so on. This paper presents a new method which extracts and selects features from multi-channel EEG signals. This research focuses on three main points. Firstly, simple random sampling (SRS) technique is used to extract features from the time domain of EEG signals. Secondly, the sequential fea...

  12. Target Selection and Deselection at the Berkeley StructuralGenomics Center

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Kim, Sung-Hou; Brenner, Steven E.

    2005-03-22

    At the Berkeley Structural Genomics Center (BSGC), our goalis to obtain a near-complete structural complement of proteins in theminimal organisms Mycoplasma genitalium and M. pneumoniae, two closelyrelated pathogens. Current targets for structure determination have beenselected in six major stages, starting with those predicted to be mosttractable to high throughput study and likely to yield new structuralinformation. We report on the process used to select these proteins, aswell as our target deselection procedure. Target deselection reducesexperimental effort by eliminating targets similar to those recentlysolved by the structural biology community or other centers. We measurethe impact of the 69 structures solved at the BSGC as of July 2004 onstructure prediction coverage of the M. pneumoniae and M. genitaliumproteomes. The number of Mycoplasma proteins for which thefold couldfirst be reliably assigned based on structures solved at the BSGC (24 M.pneumoniae and 21 M. genitalium) is approximately 25 percent of the totalresulting from work at all structural genomics centers and the worldwidestructural biology community (94 M. pneumoniae and 86M. genitalium)during the same period. As the number of structures contributed by theBSGC during that period is less than 1 percent of the total worldwideoutput, the benefits of a focused target selection strategy are apparent.If the structures of all current targets were solved, the percentage ofM. pneumoniae proteins for which folds could be reliably assigned wouldincrease from approximately 57 percent (391 of 687) at present to around80 percent (550 of 687), and the percentage of the proteome that could beaccurately modeled would increase from around 37 percent (254 of 687) toabout 64 percent (438 of 687). In M. genitalium, the percentage of theproteome that could be structurally annotated based on structures of ourremaining targets would rise from 72 percent (348 of 486) to around 76percent (371 of 486), with the

  13. Targeted drugs for pulmonary arterial hypertension: a network meta-analysis of 32 randomized clinical trials

    Directory of Open Access Journals (Sweden)

    Gao XF

    2017-05-01

    Full Text Available Xiao-Fei Gao,1 Jun-Jie Zhang,1,2 Xiao-Min Jiang,1 Zhen Ge,1,2 Zhi-Mei Wang,1 Bing Li,1 Wen-Xing Mao,1 Shao-Liang Chen1,2 1Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 2Department of Cardiology, Nanjing Heart Center, Nanjing, People’s Republic of China Background: Pulmonary arterial hypertension (PAH is a devastating disease and ultimately leads to right heart failure and premature death. A total of four classical targeted drugs, prostanoids, endothelin receptor antagonists (ERAs, phosphodiesterase 5 inhibitors (PDE-5Is, and soluble guanylate cyclase stimulator (sGCS, have been proved to improve exercise capacity and hemodynamics compared to placebo; however, direct head-to-head comparisons of these drugs are lacking. This network meta-analysis was conducted to comprehensively compare the efficacy of these targeted drugs for PAH.Methods: Medline, the Cochrane Library, and other Internet sources were searched for randomized clinical trials exploring the efficacy of targeted drugs for patients with PAH. The primary effective end point of this network meta-analysis was a 6-minute walk distance (6MWD.Results: Thirty-two eligible trials including 6,758 patients were identified. There was a statistically significant improvement in 6MWD, mean pulmonary arterial pressure, pulmonary vascular resistance, and clinical worsening events associated with each of the four targeted drugs compared with placebo. Combination therapy improved 6MWD by 20.94 m (95% confidence interval [CI]: 6.94, 34.94; P=0.003 vs prostanoids, and 16.94 m (95% CI: 4.41, 29.47; P=0.008 vs ERAs. PDE-5Is improved 6MWD by 17.28 m (95% CI: 1.91, 32.65; P=0.028 vs prostanoids, with a similar result with combination therapy. In addition, combination therapy reduced mean pulmonary artery pressure by 3.97 mmHg (95% CI: -6.06, -1.88; P<0.001 vs prostanoids, 8.24 mmHg (95% CI: -10.71, -5.76; P<0.001 vs ERAs, 3.38 mmHg (95% CI: -6.30, -0.47; P=0.023 vs

  14. Statistical inference of selection and divergence from a time-dependent Poisson random field model.

    Directory of Open Access Journals (Sweden)

    Amei Amei

    Full Text Available We apply a recently developed time-dependent Poisson random field model to aligned DNA sequences from two related biological species to estimate selection coefficients and divergence time. We use Markov chain Monte Carlo methods to estimate species divergence time and selection coefficients for each locus. The model assumes that the selective effects of non-synonymous mutations are normally distributed across genetic loci but constant within loci, and synonymous mutations are selectively neutral. In contrast with previous models, we do not assume that the individual species are at population equilibrium after divergence. Using a data set of 91 genes in two Drosophila species, D. melanogaster and D. simulans, we estimate the species divergence time t(div = 2.16 N(e (or 1.68 million years, assuming the haploid effective population size N(e = 6.45 x 10(5 years and a mean selection coefficient per generation μ(γ = 1.98/N(e. Although the average selection coefficient is positive, the magnitude of the selection is quite small. Results from numerical simulations are also presented as an accuracy check for the time-dependent model.

  15. [Prostate cancer diagnostic by saturation randomized biopsy versus rigid targeted biopsy].

    Science.gov (United States)

    Defontaines, J; Salomon, L; Champy, C; Cholley, I; Chiaradia, M; de la Taille, A

    2017-12-01

    Optimal diagram teaming up randomized biopsy (BR) to targeted biopsy (BC) is still missing for the diagnostic of prostate cancer (CP). This study compares diagram of 6, 12 or 18 BR with or without BC rigid. Between January 2014 and May 2016, 120 patients had prostate biopsy BR and BC. Each patient had 18 BR and BC. Results compared sextant (6 BR), standard (12 BR) and saturation (18 BR) protocol with or without the adding of BC for the detection of CP. Rectal examination was normal, mean PSA at 8.99ng/mL and mean volume at 54cm 3 . It was first round for 48% of patients. Forty-four cancers were found by the group 18 BR+BC (control). The detection rate was respectively, for 6, 12 and 18 BR of 61%, 82% and 91%. The add of BC increased this detection of +27% for 6 BR+BC, +13% for 12 BR+BC and +9% for 18 BR+BC. BC found 70% of all CP. Nine percent of CP were missed by BR only. Significant CP (Gleason≥7) diagnostic was the same for 12 BR+BC and 18 BR+BC. The add of BC to BR increase the detection of CP by 10%. Twelve BR+BC is the optimal diagram for the diagnostic of CP finding 95% of CP and 97% of significant CP. 4. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  16. Estimation and implications of random errors in whole-body dosimetry for targeted radionuclide therapy

    Science.gov (United States)

    Flux, Glenn D.; Guy, Matthew J.; Beddows, Ruth; Pryor, Matthew; Flower, Maggie A.

    2002-09-01

    For targeted radionuclide therapy, the level of activity to be administered is often determined from whole-body dosimetry performed on a pre-therapy tracer study. The largest potential source of error in this method is due to inconsistent or inaccurate activity retention measurements. The main aim of this study was to develop a simple method to quantify the uncertainty in the absorbed dose due to these inaccuracies. A secondary aim was to assess the effect of error propagation from the results of the tracer study to predictive absorbed dose estimates for the therapy as a result of using different radionuclides for each. Standard error analysis was applied to the MIRD schema for absorbed dose calculations. An equation was derived to describe the uncertainty in the absorbed dose estimate due solely to random errors in activity-time data, requiring only these data as input. Two illustrative examples are given. It is also shown that any errors present in the dosimetry calculations following the tracer study will propagate to errors in predictions made for the therapy study according to the ratio of the respective effective half-lives. If the therapy isotope has a much longer physical half-life than the tracer isotope (as is the case, for example, when using 123I as a tracer for 131I therapy) the propagation of errors can be significant. The equations derived provide a simple means to estimate two potentially large sources of error in whole-body absorbed dose calculations.

  17. Selection bias and subject refusal in a cluster-randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Rochelle Yang

    2017-07-01

    Full Text Available Abstract Background Selection bias and non-participation bias are major methodological concerns which impact external validity. Cluster-randomized controlled trials are especially prone to selection bias as it is impractical to blind clusters to their allocation into intervention or control. This study assessed the impact of selection bias in a large cluster-randomized controlled trial. Methods The Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE study examined the impact of a remote pharmacist-led intervention in twelve medical offices. To assess eligibility, a standardized form containing patient demographics and medical information was completed for each screened patient. Eligible patients were approached by the study coordinator for recruitment. Both the study coordinator and the patient were aware of the site’s allocation prior to consent. Patients who consented or declined to participate were compared across control and intervention arms for differing characteristics. Statistical significance was determined using a two-tailed, equal variance t-test and a chi-square test with adjusted Bonferroni p-values. Results were adjusted for random cluster variation. Results There were 2749 completed screening forms returned to research staff with 461 subjects who had either consented or declined participation. Patients with poorly controlled diabetes were found to be significantly more likely to decline participation in intervention sites compared to those in control sites. A higher mean diastolic blood pressure was seen in patients with uncontrolled hypertension who declined in the control sites compared to those who declined in the intervention sites. However, these findings were no longer significant after adjustment for random variation among the sites. After this adjustment, females were now found to be significantly more likely to consent than males (odds ratio = 1.41; 95% confidence interval = 1.03, 1

  18. The Time-domain Spectroscopic Survey: Target Selection for Repeat Spectroscopy

    Science.gov (United States)

    MacLeod, Chelsea L.; Green, Paul J.; Anderson, Scott F.; Eracleous, Michael; Ruan, John J.; Runnoe, Jessie; Nielsen Brandt, William; Badenes, Carles; Greene, Jenny; Morganson, Eric; Schmidt, Sarah J.; Schwope, Axel; Shen, Yue; Amaro, Rachael; Lebleu, Amy; Filiz Ak, Nurten; Grier, Catherine J.; Hoover, Daniel; McGraw, Sean M.; Dawson, Kyle; Hall, Patrick B.; Hawley, Suzanne L.; Mariappan, Vivek; Myers, Adam D.; Pâris, Isabelle; Schneider, Donald P.; Stassun, Keivan G.; Bershady, Matthew A.; Blanton, Michael R.; Seo, Hee-Jong; Tinker, Jeremy; Fernández-Trincado, J. G.; Chambers, Kenneth; Kaiser, Nick; Kudritzki, R.-P.; Magnier, Eugene; Metcalfe, Nigel; Waters, Chris Z.

    2018-01-01

    As astronomers increasingly exploit the information available in the time domain, spectroscopic variability in particular opens broad new channels of investigation. Here we describe the selection algorithms for all targets intended for repeat spectroscopy in the Time Domain Spectroscopic Survey (TDSS), part of the extended Baryon Oscillation Spectroscopic Survey within the Sloan Digital Sky Survey (SDSS)-IV. Also discussed are the scientific rationale and technical constraints leading to these target selections. The TDSS includes a large “repeat quasar spectroscopy” (RQS) program delivering ∼13,000 repeat spectra of confirmed SDSS quasars, and several smaller “few-epoch spectroscopy” (FES) programs targeting specific classes of quasars as well as stars. The RQS program aims to provide a large and diverse quasar data set for studying variations in quasar spectra on timescales of years, a comparison sample for the FES quasar programs, and an opportunity for discovering rare, serendipitous events. The FES programs cover a wide variety of phenomena in both quasars and stars. Quasar FES programs target broad absorption line quasars, high signal-to-noise ratio normal broad line quasars, quasars with double-peaked or very asymmetric broad emission line profiles, binary supermassive black hole candidates, and the most photometrically variable quasars. Strongly variable stars are also targeted for repeat spectroscopy, encompassing many types of eclipsing binary systems, and classical pulsators like RR Lyrae. Other stellar FES programs allow spectroscopic variability studies of active ultracool dwarf stars, dwarf carbon stars, and white dwarf/M dwarf spectroscopic binaries. We present example TDSS spectra and describe anticipated sample sizes and results.

  19. Targeting chromatin defects in selected solid tumors based on oncogene addiction, synthetic lethality and epigenetic antagonism.

    Science.gov (United States)

    Morel, D; Almouzni, G; Soria, J-C; Postel-Vinay, S

    2017-02-01

    Although the role of epigenetic abnormalities has been studied for several years in cancer genesis and development, epigenetic-targeting drugs have historically failed to demonstrate efficacy in solid malignancies. However, successful targeting of chromatin remodeling deficiencies, histone writers and histone reader alterations has been achieved very recently using biomarker-driven and mechanism-based approaches. Epigenetic targeting is now one of the most active areas in drug development and could represent novel therapeutic opportunity for up to 25% of all solid tumors. We reviewed preclinical and clinical studies that described epigenetic oncogenic addictions, synthetic lethal relationships or epigenetic antagonisms in chromatin regulators. Experimental approaches, their clinical relevance and applicability, as well as corresponding on-going studies are described. The most successful approaches that have been clinically validated so far include the targeting of the BRD4-NUT fusion transcript in NUT-midline carcinoma by BET (Bromodomain Extra-Terminal) inhibitors, and the use of EZH2 (Enhancer of Zest Homolog 2) inhibitors in SMARCB1-deficient malignant rhabdoid tumors and SMARCA4-deficient ovarian small cell carcinomas. Clinical validation is still required for other synthetic lethal relationships or epigenetic antagonisms, including those described between EZH2 inhibitors and deficiencies in components of the Polycomb or SWI/SNF chromatin-remodeling complexes (including BAP1, ARID1A and PBRM1 subunits), as well as between the CREBBP and EP300 histone acetylases. Further, interplays between epigenetic modifiers and non-epigenetic cellular processes might be therapeutically exploited, and combinatorial strategies could be envisioned to overcome resistance or to sensitize cells to already approved drugs. Epigenetic-targeting drugs have historically failed proving efficacy in solid malignancies when used broadly, but novel mechanism-based approaches in molecularly

  20. Sequential Retraction Segregates SGN Processes during Target Selection in the Cochlea

    Science.gov (United States)

    Druckenbrod, Noah R.

    2015-01-01

    A hallmark of the nervous system is the presence of precise patterns of connections between different types of neurons. Many mechanisms can be used to establish specificity, including homophilic adhesion and synaptic refinement, but the range of strategies used across the nervous system remains unclear. To broaden the understanding of how neurons find their targets, we studied the developing murine cochlea, where two classes of spiral ganglion neurons (SGNs), type I and type II, navigate together to the sensory epithelium and then diverge to contact inner hair cells (IHCs) or outer hair cells (OHCs), respectively. Neurons with type I and type II morphologies are apparent before birth, suggesting that target selection might be accomplished by excluding type I processes from the OHC region. However, because type I processes appear to overshoot into type II territory postnatally, specificity may also depend on elimination of inappropriate synapses. To resolve these differences, we analyzed the morphology and dynamic behaviors of individual fibers and their branches as they interact with potential partners. We found that SGN processes continue to be segregated anatomically in the postnatal cochlea. Although type I-like fibers branched locally, few branches contacted OHCs, arguing against synaptic elimination. Instead, time-lapse imaging studies suggest a prominent role for retraction, first positioning processes to the appropriate region and then corralling branches during a subsequent period of exuberant growth and refinement. Thus, sequential stages of retraction can help to achieve target specificity, adding to the list of mechanisms available for sculpting neural circuits. SIGNIFICANCE STATEMENT During development, different types of neurons must form connections with specific synaptic targets, thereby creating the precise wiring diagram necessary for adult function. Although studies have revealed multiple mechanisms for target selection, we still know little about

  1. Target Selection for the LBTI Hunt for Observable Signatures of Terrestrial Planetary Systems

    Science.gov (United States)

    Roberge, A.; Weinberger, A.; Kennedy, G.; Defrère, D.; LBTI Instrument; Science Teams

    2014-03-01

    The Hunt for Observable Signatures of Terrestrial planetary Systems (HOSTS) on the Large Binocular Telescope Interferometer (LBTI) will survey nearby stars for faint exozodiacal dust (exozodi). This warm circumstellar dust, analogous to the interplanetary dust found in the vicinity of the Earth in our own system, is produced in comet breakups and asteroid collisions. Exozodi will be the major source of astrophysical noise for a future space telescope aimed at direct imaging and spectroscopy of habitable zone terrestrial planets (exo-Earths). About 20% of nearby field stars have cold dust coming from planetesimals at large distances from the stars (Eiroa et al. 2013). Much less is known about exozodi; current detection limits for individual stars are at best ~ 500 times our solar system's level (aka. 500 zodi). LBTI-HOSTS will be the first survey capable of measuring exozodi at the 10 zodi level (3s). Detections of warm dust will also reveal new information about planetary system architectures and evolution. We describe the target star selection by the LBTI Science Team to satisfy the goals of the HOSTS survey - to inform mission design and target selection for a future exo-Earth mission. We are interested in both 1) actual stars likely to be observed by such a mission and 2) stars whose observation will enable sensible extrapolations for stars that cannot be observed with LBTI. We integrated two approaches to generate the HOSTS target list. The mission-driven approach concentrates on F, G, and K-type stars that are the best targets for future direct observations of exo-Earths, thereby providing model-independent "ground truth" dust observations. However, not every potential target of a future exo-Earth mission can be observed with LBTI. The sensitivity-driven approach selects targets based on maximizing the exozodi sensitivity that can be achieved, without consideration of exo-Earth mission constraints. This naturally chooses more luminous stars (A and early F

  2. The impact of nurse-driven targeted HIV screening in 8 emergency departments: study protocol for the DICI-VIH cluster-randomized two-period crossover trial.

    Science.gov (United States)

    Leblanc, Judith; Rousseau, Alexandra; Hejblum, Gilles; Durand-Zaleski, Isabelle; de Truchis, Pierre; Lert, France; Costagliola, Dominique; Simon, Tabassome; Crémieux, Anne-Claude

    2016-02-01

    In 2010, to reduce late HIV diagnosis, the French national health agency endorsed non-targeted HIV screening in health care settings. Despite these recommendations, non-targeted screening has not been implemented and only physician-directed diagnostic testing is currently performed. A survey conducted in 2010 in 29 French Emergency Departments (EDs) showed that non-targeted nurse-driven screening was feasible though only a few new HIV diagnoses were identified, predominantly among high-risk groups. A strategy targeting high-risk groups combined with current practice could be shown to be feasible, more efficient and cost-effective than current practice alone. DICI-VIH (acronym for nurse-driven targeted HIV screening) is a multicentre, cluster-randomized, two-period crossover trial. The primary objective is to compare the effectiveness of 2 strategies for diagnosing HIV among adult patients visiting EDs: nurse-driven targeted HIV screening combined with current practice (physician-directed diagnostic testing) versus current practice alone. Main secondary objectives are to compare access to specialist consultation and how early HIV diagnosis occurs in the course of the disease between the 2 groups, and to evaluate the implementation, acceptability and cost-effectiveness of nurse-driven targeted screening. The 2 strategies take place during 2 randomly assigned periods in 8 EDs of metropolitan Paris, where 42 % of France's new HIV patients are diagnosed every year. All patients aged 18 to 64, not presenting secondary to HIV exposure are included. During the intervention period, patients are invited to fill a 7-item questionnaire (country of birth, sexual partners and injection drug use) in order to select individuals who are offered a rapid test. If the rapid test is reactive, a follow-up visit with an infectious disease specialist is scheduled within 72 h. Assuming an 80 % statistical power and a 5 % type 1 error, with 1.04 and 3.38 new diagnoses per 10,000 patients in

  3. Insonation frequency selection may assist detection and therapeutic delivery of targeted ultrasound contrast agents.

    Science.gov (United States)

    Payne, Edward; Ooi, Andrew; Manasseh, Richard

    2011-02-01

    Ultrasound-targeted drug delivery relies on the unique nature of ultrasound contrast agents--they are microbubbles that respond strongly to ultrasound. Intravenously injected microbubbles are smaller than a blood cell. By increasing the ultrasound power, the bubbles can be ruptured at the targeted endothelial wall, locally releasing any molecules in the bubble shell. Furthermore, ultrasound-activated microbubbles are known to cause sonoporation--the process by which ultrasound drives molecules through cellular membranes. However, techniques are required to selectively detect and rupture only those microbubbles on target walls. Experiments are presented on the behaviour of microbubbles on walls. For accuracy, imaging measurements are made on model microbubbles larger than contrast agents. Bubble size was varied and the resonant frequency peak determined. Microbubbles on walls have a shifted frequency in good agreement with theory: a 20-25% downshift from the frequency when far from walls. Effects other than the presence of the wall account for less than 5% of the shift. Theory predicts the frequency downshift should be sustained for actual contrast-agent sized bubbles. The effect of real, compliant cell walls requires investigation. An appropriate downshift in the applied ultrasound frequency could selectively tune gene or drug delivery. To make this feasible, it may be necessary to manufacture monodispersed microbubbles.

  4. The SDSS-IV extended Baryon Oscillation Spectroscopic Survey: final emission line galaxy target selection

    Science.gov (United States)

    Raichoor, A.; Comparat, J.; Delubac, T.; Kneib, J.-P.; Yèche, Ch; Dawson, K. S.; Percival, W. J.; Dey, A.; Lang, D.; Schlegel, D. J.; Gorgoni, C.; Bautista, J.; Brownstein, J. R.; Mariappan, V.; Seo, H.-J.; Tinker, J. L.; Ross, A. J.; Wang, Y.; Zhao, G.-B.; Moustakas, J.; Palanque-Delabrouille, N.; Jullo, E.; Newmann, J. A.; Prada, F.; Zhu, G. B.

    2017-11-01

    We describe the algorithm used to select the emission line galaxy (ELG) sample at z ˜ 0.85 for the extended Baryon Oscillation Spectroscopic Survey of the Sloan Digital Sky Survey IV, using photometric data from the DECam Legacy Survey. Our selection is based on a selection box in the g - r versus r - z colour-colour space and a cut on the g-band magnitude, to favour galaxies in the desired redshift range with strong [O II] emission. It provides a target density of 200 deg-2 on the North Galactic Cap and of 240 deg-2 on the South Galactic Cap (SGC), where we use a larger selection box because of deeper imaging. We demonstrate that this selection passes the extended Baryon Oscillation Spectroscopic Survey requirements in terms of homogeneity. About 50 000 ELGs have been observed since the observations have started in 2016, September. These roughly match the expected redshift distribution, though the measured efficiency is slightly lower than expected. The efficiency can be increased by enlarging the redshift range and with incoming pipeline improvement. The cosmological forecast based on these first data predict σ _{D_V}/D_V = 0.023, in agreement with previous forecasts. Lastly, we present the stellar population properties of the ELG SGC sample. Once observations are completed, this sample will be suited to provide a cosmological analysis at z ˜ 0.85, and will pave the way for the next decade of massive spectroscopic cosmological surveys, which heavily rely on ELGs. The target catalogue over the SGC will be released along with DR14.

  5. Effect of non-random mating on genomic and BLUP selection schemes

    Directory of Open Access Journals (Sweden)

    Nirea Kahsay G

    2012-04-01

    Full Text Available Abstract Background The risk of long-term unequal contribution of mating pairs to the gene pool is that deleterious recessive genes can be expressed. Such consequences could be alleviated by appropriately designing and optimizing breeding schemes i.e. by improving selection and mating procedures. Methods We studied the effect of mating designs, random, minimum coancestry and minimum covariance of ancestral contributions on rate of inbreeding and genetic gain for schemes with different information sources, i.e. sib test or own performance records, different genetic evaluation methods, i.e. BLUP or genomic selection, and different family structures, i.e. factorial or pair-wise. Results Results showed that substantial differences in rates of inbreeding due to mating design were present under schemes with a pair-wise family structure, for which minimum coancestry turned out to be more effective to generate lower rates of inbreeding. Specifically, substantial reductions in rates of inbreeding were observed in schemes using sib test records and BLUP evaluation. However, with a factorial family structure, differences in rates of inbreeding due mating designs were minor. Moreover, non-random mating had only a small effect in breeding schemes that used genomic evaluation, regardless of the information source. Conclusions It was concluded that minimum coancestry remains an efficient mating design when BLUP is used for genetic evaluation or when the size of the population is small, whereas the effect of non-random mating is smaller in schemes using genomic evaluation.

  6. Screen-Time Weight-loss Intervention Targeting Children at Home (SWITCH): a randomized controlled trial.

    Science.gov (United States)

    Maddison, Ralph; Marsh, Samantha; Foley, Louise; Epstein, Leonard H; Olds, Timothy; Dewes, Ofa; Heke, Ihirangi; Carter, Karen; Jiang, Yannan; Mhurchu, Cliona Ni

    2014-09-10

    Screen-based activities, such as watching television (TV), playing video games, and using computers, are common sedentary behaviors among young people and have been linked with increased energy intake and overweight. Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child, small sample sizes, and short follow-up periods. The SWITCH (Screen-Time Weight-loss Intervention Targeting Children at Home) study aimed to determine the effect of a home-based, family-delivered intervention to reduce screen-based sedentary behaviour on body composition, sedentary behaviour, physical activity, and diet over 24 weeks in overweight and obese children. A two-arm, parallel, randomized controlled trial was conducted. Children and their primary caregiver living in Auckland, New Zealand were recruited via schools, community centres, and word of mouth. The intervention, delivered over 20 weeks, consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content, which focused on training and educating them to use a wide range of strategies designed to reduce their child's screen time. Families were given Time Machine TV monitoring devices to assist with allocating screen time, activity packages to promote alternative activities, online support via a website, and monthly newsletters. Control participants were given the intervention material on completion of follow-up. The primary outcome was change in children's BMI z-score from baseline to 24 weeks. Children (n = 251) aged 9-12 years and their primary caregiver were randomized to receive the SWITCH intervention (n = 127) or no intervention (controls; n = 124). There was no significant difference in change of zBMI between the intervention and control groups, although a favorable trend was observed (-0.016; 95% CI: -0.084, 0.051; p = 0.64). There were also no significant differences on secondary outcomes, except for a trend towards

  7. "Killer" Microcapsules That Can Selectively Destroy Target Microparticles in Their Vicinity.

    Science.gov (United States)

    Arya, Chandamany; Oh, Hyuntaek; Raghavan, Srinivasa R

    2016-11-02

    We have developed microscale polymer capsules that are able to chemically degrade a certain type of polymeric microbead in their immediate vicinity. The inspiration here is from the body's immune system, where killer T cells selectively destroy cancerous cells or cells infected by pathogens while leaving healthy cells alone. The "killer" capsules are made from the cationic biopolymer chitosan by a combination of ionic cross-linking (using multivalent tripolyposphate anions) and subsequent covalent cross-linking (using glutaraldehyde). During capsule formation, the enzyme glucose oxidase (GOx) is encapsulated in these capsules. The target beads are made by ionic cross-linking of the biopolymer alginate using copper (Cu(2+)) cations. The killer capsules harvest glucose from their surroundings, which is then enzymatically converted by GOx into gluconate ions. These ions are known for their ability to chelate Cu(2+) cations. Thus, when a killer capsule is next to a target alginate bead, the gluconate ions diffuse into the bead and extract the Cu(2+) cross-links, causing the disintegration of the target bead. Such destruction is visualized in real-time using optical microscopy. The destruction is specific, i.e., other microparticles that do not contain Cu(2+) are left undisturbed. Moreover, the destruction is localized, i.e., the targets destroyed in the short term are the ones right next to the killer beads. The time scale for destruction depends on the concentration of encapsulated enzyme in the capsules.

  8. Antisense oligonucleotides targeting translation inhibitory elements in 5' UTRs can selectively increase protein levels.

    Science.gov (United States)

    Liang, Xue-Hai; Sun, Hong; Shen, Wen; Wang, Shiyu; Yao, Joyee; Migawa, Michael T; Bui, Huynh-Hoa; Damle, Sagar S; Riney, Stan; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T

    2017-09-19

    A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5' UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5' UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5' UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  9. K-Ras(G12D)-selective inhibitory peptides generated by random peptide T7 phage display technology.

    Science.gov (United States)

    Sakamoto, Kotaro; Kamada, Yusuke; Sameshima, Tomoya; Yaguchi, Masahiro; Niida, Ayumu; Sasaki, Shigekazu; Miwa, Masanori; Ohkubo, Shoichi; Sakamoto, Jun-Ichi; Kamaura, Masahiro; Cho, Nobuo; Tani, Akiyoshi

    2017-03-11

    Amino-acid mutations of Gly 12 (e.g. G12D, G12V, G12C) of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), the most promising drug target in cancer therapy, are major growth drivers in various cancers. Although over 30 years have passed since the discovery of these mutations in most cancer patients, effective mutated K-Ras inhibitors have not been marketed. Here, we report novel and selective inhibitory peptides to K-Ras(G12D). We screened random peptide libraries displayed on T7 phage against purified recombinant K-Ras(G12D), with thorough subtraction of phages bound to wild-type K-Ras, and obtained KRpep-2 (Ac-RRCPLYISYDPVCRR-NH 2 ) as a consensus sequence. KRpep-2 showed more than 10-fold binding- and inhibition-selectivity to K-Ras(G12D), both in SPR analysis and GDP/GTP exchange enzyme assay. K D and IC 50 values were 51 and 8.9 nM, respectively. After subsequent sequence optimization, we successfully generated KRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH 2 ) that inhibited enzyme activity of K-Ras(G12D) with IC 50  = 1.6 nM and significantly suppressed ERK-phosphorylation, downstream of K-Ras(G12D), along with A427 cancer cell proliferation at 30 μM peptide concentration. To our knowledge, this is the first report of a K-Ras(G12D)-selective inhibitor, contributing to the development and study of K-Ras(G12D)-targeting drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Economic assessment of FEC-based targeted selective drenching in horses.

    Science.gov (United States)

    Sallé, Guillaume; Cortet, Jacques; Koch, Christine; Reigner, Fabrice; Cabaret, Jacques

    2015-11-30

    In the face of an increased prevalence of drug-resistant cyathostomin populations, a targeted selective treatment (TST) strategy based on Faecal Egg Counts (FECs) has been proposed as an alternative management strategy. However, associated costs may be a barrier to the uptake of this strategy. Our study aims to provide an economic assessment of FEC-based TST. FECs were determined in a Welsh pony herd thrice a year from 2010 to 2014. This database was used to explore the impact of FEC price, sampling strategy (individual or pooled) and labour-associated costs. Drug price was set at the cheapest level, hence providing a conservative framework to determine the maximum viable FEC price in the context of a cost-driven horse industry. The maximum viable FEC price for a cost-efficient individual based strategy was determined by an in silico bootstrap approach consisting of randomly sampling 1000 virtual pony herds of various sizes (1 to 100 ponies) from the available database and estimating the associated costs (FEC price ranging from € 1 to € 10, anthelmintic costs and labour-associated costs). The costs and benefits of the pooling strategy that consists of basing the decision to treat on group FEC values were also investigated. This is thought to reduce FEC-based costs but may result in highly infected individuals being left undrenched, i.e. in false-negatives, as a result of FEC overdispersion. For various pool-sizes (1-20 ponies) and various cut-off thresholds (50-200 eggs/g), we sampled 1000 pony herds in silico to estimate the associated costs and determine the number of positive ponies within a negative pool. Following these simulations, pool-based FECs of various sizes were performed on 40 ponies to compare predictions with real data. Within 4 years, anthelmintic costs were cut by 80%, albeit with free FECs. In silico estimations suggested that an individual FEC-based TST would not be cost-efficient in this context for an FEC price above € 5. With a pooled

  11. The Gaia Survey Contribution to EChO Target Selection and Characterization

    OpenAIRE

    Sozzetti, A.; Damasso, M.

    2014-01-01

    The scientific output of the proposed EChO mission (in terms of spectroscopic characterization of the atmospheres of transiting extrasolar planets) will be maximized by a careful selection of targets and by a detailed characterization of the main physical parameters (such as masses and radii) of both the planets and their stellar hosts. To achieve this aim, the availability of high-quality data from other space-borne and ground-based programs will play a crucial role. Here we identify and dis...

  12. Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance?

    Science.gov (United States)

    Leathwick, Dave M; Luo, Dongwen

    2017-08-30

    The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose-response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Covariance-based band selection and its application to near-real-time hyperspectral target detection

    Science.gov (United States)

    Kim, Jun-Hyung; Kim, Jieun; Yang, Yukyung; Kim, Sohyun; Kim, Hyun Sook

    2017-05-01

    The matched filter (MF) and adaptive coherence estimator (ACE) show great effectiveness in hyperspectral target detection applications. Practical applications in which on-board processing is generally required demand real-time or near-real-time implementation of these detectors. However, a vast amount of hyperspectral data may make real-time or near-real-time implementation of the detection algorithms almost impossible. Band selection can be one of the solutions to this problem by reducing the number of spectral bands. We propose a new band selection method that prioritizes spectral bands based on their influence on the detection performance of the MF and ACE and discards the least influential bands. We validate the performance of our method using real hyperspectral images. We also demonstrate our technique on near-real-time detection tasks and show it to be a feasible approach to the tasks.

  14. SPARSE: Seed Point Auto-Generation for Random Walks Segmentation Enhancement in medical inhomogeneous targets delineation of morphological MR and CT images.

    Science.gov (United States)

    Chen, Haibin; Zhen, Xin; Gu, Xuejun; Yan, Hao; Cervino, Laura; Xiao, Yang; Zhou, Linghong

    2015-03-08

    In medical image processing, robust segmentation of inhomogeneous targets is a challenging problem. Because of the complexity and diversity in medical images, the commonly used semiautomatic segmentation algorithms usually fail in the segmentation of inhomogeneous objects. In this study, we propose a novel algorithm imbedded with a seed point autogeneration for random walks segmentation enhancement, namely SPARSE, for better segmentation of inhomogeneous objects. With a few user-labeled points, SPARSE is able to generate extended seed points by estimating the probability of each voxel with respect to the labels. The random walks algorithm is then applied upon the extended seed points to achieve improved segmentation result. SPARSE is implemented under the compute unified device architecture (CUDA) programming environment on graphic processing unit (GPU) hardware platform. Quantitative evaluations are performed using clinical homogeneous and inhomogeneous cases. It is found that the SPARSE can greatly decrease the sensitiveness to initial seed points in terms of location and quantity, as well as the freedom of selecting parameters in edge weighting function. The evaluation results of SPARSE also demonstrate substantial improvements in accuracy and robustness to inhomogeneous target segmentation over the original random walks algorithm.

  15. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seula [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Woo, Jong Kyu [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Oh, Seung Hyun [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Ryu, Jae-Ha [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Kim, Woo-Young, E-mail: wykim@sookmyung.ac.kr [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of)

    2016-01-22

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.

  16. Criteria for selection of target materials and design of high-efficiency-release targets for radioactive ion beam generation

    CERN Document Server

    Alton, G D; Liu, Y

    1999-01-01

    In this report, we define criteria for choosing target materials and for designing, mechanically stable, short-diffusion-length, highly permeable targets for generation of high-intensity radioactive ion beams (RIBs) for use at nuclear physics and astrophysics research facilities based on the ISOL principle. In addition, lists of refractory target materials are provided and examples are given of a number of successful targets, based on these criteria, that have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF).

  17. Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

    Energy Technology Data Exchange (ETDEWEB)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-01

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

  18. Novel Zn2+-chelating peptides selected from a fimbria-displayed random peptide library

    DEFF Research Database (Denmark)

    Kjærgaard, Kristian; Schembri, Mark; Klemm, Per

    2001-01-01

    H adhesin. FimH is a component of the fimbrial organelle that can accommodate and display a diverse range of peptide sequences on the E. coli cell surface. In this study we have constructed a random peptide library in FimH. The library, consisting of similar to 40 million individual clones, was screened...... for peptide sequences that conferred on recombinant cells the ability to bind Zn2+. By serial selection, sequences that exhibited various degrees of binding affinity and specificity toward Zn2+ were enriched. None of the isolated sequences showed similarity to known Zn2+-binding proteins, indicating...

  19. Prevention of anxiety disorders and depression by targeting excessive worry and rumination in adolescents and young adults: A randomized controlled trial.

    Science.gov (United States)

    Topper, Maurice; Emmelkamp, Paul M G; Watkins, Ed; Ehring, Thomas

    2017-03-01

    This randomized controlled trial evaluated the efficacy of a preventive intervention for anxiety disorders and depression by targeting excessive levels of repetitive negative thinking (RNT; worry and rumination) in adolescents and young adults. Participants (N = 251, 83.7% female) showing elevated levels of RNT were randomly allocated to a 6-week cognitive-behavioral training delivered in a group, via the internet, or to a waitlist control condition. Self-report measures were collected at pre-intervention, post-intervention, 3 m and 12 m follow-up. Both versions of the preventive intervention significantly reduced RNT (d = 0.53 to 0.89), and symptom levels of anxiety and depression (d = 0.36 to 0.72). Effects were maintained until 12 m follow-up. The interventions resulted in a significantly lower 12 m prevalence rate of depression (group intervention: 15.3%, internet intervention: 14.7%) and generalized anxiety disorder (group intervention: 18.0%, internet intervention: 16.0%), compared to the waitlist (32.4% and 42.2%, respectively). Mediation analyses demonstrated that reductions in RNT mediated the effect of the interventions on the prevalence of depression and generalized anxiety disorder. Results provide evidence for the efficacy of this preventive intervention targeting RNT and support a selective prevention approach that specifically targets a known risk factor to prevent multiple disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Assessing the accuracy and stability of variable selection methods for random forest modeling in ecology.

    Science.gov (United States)

    Fox, Eric W; Hill, Ryan A; Leibowitz, Scott G; Olsen, Anthony R; Thornbrugh, Darren J; Weber, Marc H

    2017-07-01

    Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological data sets, there is limited guidance on variable selection methods for RF modeling. Typically, either a preselected set of predictor variables are used or stepwise procedures are employed which iteratively remove variables according to their importance measures. This paper investigates the application of variable selection methods to RF models for predicting probable biological stream condition. Our motivating data set consists of the good/poor condition of n = 1365 stream survey sites from the 2008/2009 National Rivers and Stream Assessment, and a large set (p = 212) of landscape features from the StreamCat data set as potential predictors. We compare two types of RF models: a full variable set model with all 212 predictors and a reduced variable set model selected using a backward elimination approach. We assess model accuracy using RF's internal out-of-bag estimate, and a cross-validation procedure with validation folds external to the variable selection process. We also assess the stability of the spatial predictions generated by the RF models to changes in the number of predictors and argue that model selection needs to consider both accuracy and stability. The results suggest that RF modeling is robust to the inclusion of many variables of moderate to low importance. We found no substantial improvement in cross-validated accuracy as a result of variable reduction. Moreover, the backward elimination procedure tended to select too few variables and exhibited numerous issues such as upwardly biased out-of-bag accuracy estimates and instabilities in the spatial predictions. We use simulations to further support and generalize results from the analysis of real data. A main purpose of this work is to elucidate issues of model selection bias and instability to ecologists interested in

  1. Selective pressures for accurate altruism targeting: evidence from digital evolution for difficult-to-test aspects of inclusive fitness theory.

    Science.gov (United States)

    Clune, Jeff; Goldsby, Heather J; Ofria, Charles; Pennock, Robert T

    2011-03-07

    Inclusive fitness theory predicts that natural selection will favour altruist genes that are more accurate in targeting altruism only to copies of themselves. In this paper, we provide evidence from digital evolution in support of this prediction by competing multiple altruist-targeting mechanisms that vary in their accuracy in determining whether a potential target for altruism carries a copy of the altruist gene. We compete altruism-targeting mechanisms based on (i) kinship (kin targeting), (ii) genetic similarity at a level greater than that expected of kin (similarity targeting), and (iii) perfect knowledge of the presence of an altruist gene (green beard targeting). Natural selection always favoured the most accurate targeting mechanism available. Our investigations also revealed that evolution did not increase the altruism level when all green beard altruists used the same phenotypic marker. The green beard altruism levels stably increased only when mutations that changed the altruism level also changed the marker (e.g. beard colour), such that beard colour reliably indicated the altruism level. For kin- and similarity-targeting mechanisms, we found that evolution was able to stably adjust altruism levels. Our results confirm that natural selection favours altruist genes that are increasingly accurate in targeting altruism to only their copies. Our work also emphasizes that the concept of targeting accuracy must include both the presence of an altruist gene and the level of altruism it produces.

  2. Target objects defined by a conjunction of colour and shape can be selected independently and in parallel.

    Science.gov (United States)

    Jenkins, Michael; Grubert, Anna; Eimer, Martin

    2017-11-01

    It is generally assumed that during search for targets defined by a feature conjunction, attention is allocated sequentially to individual objects. We tested this hypothesis by tracking the time course of attentional processing biases with the N2pc component in tasks where observers searched for two targets defined by a colour/shape conjunction. In Experiment 1, two displays presented in rapid succession (100 ms or 10 ms SOA) each contained a target and a colour-matching or shape-matching distractor on opposite sides. Target objects in both displays elicited N2pc components of similar size that overlapped in time when the SOA was 10 ms, suggesting that attention was allocated in parallel to both targets. Analogous results were found in Experiment 2, where targets and partially matching distractors were both accompanied by an object without target-matching features. Colour-matching and shape-matching distractors also elicited N2pc components, and the target N2pc was initially identical to the sum of the two distractor N2pcs, suggesting that the initial phase of attentional object selection was guided independently by feature templates for target colour and shape. Beyond 230 ms after display onset, the target N2pc became superadditive, indicating that attentional selection processes now started to be sensitive to the presence of feature conjunctions. Results show that independent attentional selection processes can be activated in parallel by two target objects in situations where these objects are defined by a feature conjunction.

  3. Update on the Pfam5000 Strategy for Selection of StructuralGenomics Targets

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Brenner, Steven E.

    2005-06-27

    Structural Genomics is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy that is medically and biologically relevant, of good financial value, and tractable. In 2003, we presented the ''Pfam5000'' strategy, which involves selecting the 5,000 most important families from the Pfam database as sources for targets. In this update, we show that although both the Pfam database and the number of sequenced genomes have increased in size, the expected benefits of the Pfam5000 strategy have not changed substantially. Solving the structures of proteins from the 5,000 largest Pfam families would allow accurate fold assignment for approximately 65 percent of all prokaryotic proteins (covering 54 percent of residues) and 63 percent of eukaryotic proteins (42 percent of residues). Fewer than 2,300 of the largest families on this list remain to be solved, making the project feasible in the next five years given the expected throughput to be achieved in the production phase of the Protein Structure Initiative.

  4. Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1

    Directory of Open Access Journals (Sweden)

    Hirotada Tajiri

    2017-05-01

    Full Text Available Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells. By screening chemical libraries, we have identified 1-(2-(3′-(trifluoromethyl-[1,1′-biphenyl]-4-yl-2-oxoethyl-5-pyrrolidinylsulfonyl-2(1H-pyridone (TBOPP as a selective inhibitor of DOCK1. TBOPP dampened DOCK1-mediated invasion, macropinocytosis, and survival under the condition of glutamine deprivation without impairing the biological functions of the closely related DOCK2 and DOCK5 proteins. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. Our results demonstrate that selective pharmacological inhibition of DOCK1 could be a therapeutic approach to target cancer cell survival and invasion.

  5. Does Angling Technique Selectively Target Fishes Based on Their Behavioural Type?

    Directory of Open Access Journals (Sweden)

    Alexander D M Wilson

    Full Text Available Recently, there has been growing recognition that fish harvesting practices can have important impacts on the phenotypic distributions and diversity of natural populations through a phenomenon known as fisheries-induced evolution. Here we experimentally show that two common recreational angling techniques (active crank baits versus passive soft plastics differentially target wild largemouth bass (Micropterus salmoides and rock bass (Ambloplites rupestris based on variation in their behavioural tendencies. Fish were first angled in the wild using both techniques and then brought back to the laboratory and tested for individual-level differences in common estimates of personality (refuge emergence, flight-initiation-distance, latency-to-recapture and with a net, and general activity in an in-lake experimental arena. We found that different angling techniques appear to selectively target these species based on their boldness (as characterized by refuge emergence, a standard measure of boldness in fishes but not other assays of personality. We also observed that body size was independently a significant predictor of personality in both species, though this varied between traits and species. Our results suggest a context-dependency for vulnerability to capture relative to behaviour in these fish species. Ascertaining the selective pressures angling practices exert on natural populations is an important area of fisheries research with significant implications for ecology, evolution, and resource management.

  6. PReFerSim: fast simulation of demography and selection under the Poisson Random Field model.

    Science.gov (United States)

    Ortega-Del Vecchyo, Diego; Marsden, Clare D; Lohmueller, Kirk E

    2016-11-15

    The Poisson Random Field (PRF) model has become an important tool in population genetics to study weakly deleterious genetic variation under complicated demographic scenarios. Currently, there are no freely available software applications that allow simulation of genetic variation data under this model. Here we present PReFerSim, an ANSI C program that performs forward simulations under the PRF model. PReFerSim models changes in population size, arbitrary amounts of inbreeding, dominance and distributions of selective effects. Users can track summaries of genetic variation over time and output trajectories of selected alleles. PReFerSim is freely available at: https://github.com/LohmuellerLab/PReFerSim CONTACT: klohmueller@ucla.eduSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Multibranched Gold Nanoparticles with Intrinsic LAT-1 Targeting Capabilities for Selective Photothermal Therapy of Breast Cancer.

    Science.gov (United States)

    Ong, Zhan Yuin; Chen, Shu; Nabavi, Elham; Regoutz, Anna; Payne, David J; Elson, Daniel S; Dexter, David T; Dunlop, Iain E; Porter, Alexandra E

    2017-11-15

    Because of the critical role of the large neutral amino acid transporter-1 (LAT-1) in promoting tumor growth and proliferation, it is fast emerging as a highly attractive biomarker for the imaging and treatment of human malignancies, including breast cancer. While multibranched gold nanoparticles (AuNPs) have emerged as a promising modality in the photothermal therapy (PTT) of cancers, some of the key challenges limiting their clinical translation lie in the need to develop reproducible and cost-effective synthetic methods as well as the selective accumulation of sufficient AuNPs at tumor sites. In this study, we report a simple and direct seed-mediated synthesis of monodispersed multibranched AuNPs using the catechol-containing LAT-1 ligands, L- and D-dopa, to confer active cancer targeting. This route obviates the need for additional conjugation with targeting moieties such as peptides or antibodies. Nanoflower-like AuNPs (AuNF) with diameters of approximately 46, 70, and 90 nm were obtained and were found to possess excellent colloidal stability and biocompatibility. A significantly higher intracellular accumulation of the L- and D-dopa functionalized AuNFs was observed in a panel of breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-468, and MDA-MB-453) when compared to the nontargeting control AuNFs synthesized with dopamine and 4-ethylcatechol. Importantly, no significant difference in uptake between the targeting and nontargeting AuNFs was observed in a non-tumorigenic MCF-10A breast epithelial cell line, hence demonstrating tumor selectivity. For PTT of breast cancer, Ag+ was introduced during synthesis to obtain L-dopa functionalized nanourchin-like AuNPs (AuNUs) with strong near-infrared (NIR) absorbance. The L-dopa functionalized AuNUs mediated selective photothermal ablation of the triple negative MDA-MB-231 breast cancer cell line and sensitized the cells to the anticancer drugs cisplatin and docetaxel. This work brings forward an effective strategy

  8. Personalized Antidepressant Selection and Pathway to Novel Treatments: Clinical Utility of Targeting Inflammation

    Directory of Open Access Journals (Sweden)

    Manish K. Jha

    2018-01-01

    Full Text Available Major depressive disorder (MDD is a chronic condition that affects one in six adults in the US during their lifetime. The current practice of antidepressant medication prescription is a trial-and-error process. Additionally, over a third of patients with MDD fail to respond to two or more antidepressant treatments. There are no valid clinical markers to personalize currently available antidepressant medications, all of which have similar mechanisms targeting monoamine neurotransmission. The goal of this review is to summarize the recent findings of immune dysfunction in patients with MDD, the utility of inflammatory markers to personalize treatment selection, and the potential of targeting inflammation to develop novel antidepressant treatments. To personalize antidepressant prescription, a c-reactive protein (CRP-matched treatment assignment can be rapidly implemented in clinical practice with point-of-care fingerstick tests. With this approach, 4.5 patients need to be treated for 1 additional remission as compared to a CRP-mismatched treatment assignment. Anti-cytokine treatments may be effective as novel antidepressants. Monoclonal antibodies against proinflammatory cytokines, such as interleukin 6, interleukin 17, and tumor necrosis factor α, have demonstrated antidepressant effects in patients with chronic inflammatory conditions who report significant depressive symptoms. Additional novel antidepressant strategies targeting inflammation include pharmaceutical agents that block the effect of systemic inflammation on the central nervous system. In conclusion, inflammatory markers offer the potential not only to personalize antidepressant prescription but also to guide the development of novel mechanistically-guided antidepressant treatments.

  9. Scientific objectives and selection of targets for the SMART-1 Infrared Spectrometer (SIR)

    Science.gov (United States)

    Basilevsky, A.T.; Keller, H.U.; Nathues, A.; Mall, U.; Hiesinger, H.; Rosiek, M.

    2004-01-01

    The European SMART-1 mission to the Moon, primarily a testbed for innovative technologies, was launched in September 2003 and will reach the Moon in 2005. On board are several scientific instruments, including the point-spectrometer SMART-1 Infrared Spectrometer (SIR). Taking into account the capabilities of the SMART-1 mission and the SIR instrument in particular, as well as the open questions in lunar science, a selection of targets for SIR observations has been compiled. SIR can address at least five topics: (1) Surface/regolith processes; (2) Lunar volcanism; (3) Lunar crust structure; (4) Search for spectral signatures of ices at the lunar poles; and (5) Ground truth and study of geometric effects on the spectral shape. For each topic we will discuss specific observation modes, necessary to achieve our scientific goals. The majority of SIR targets will be observed in the nadir-tracking mode. More than 100 targets, which require off-nadir pointing and off-nadir tracking, are planned. It is expected that results of SIR observations will significantly increase our understanding of the Moon. Since the exact arrival date and the orbital parameters of the SMART-1 spacecraft are not known yet, a more detailed planning of the scientific observations will follow in the near future. ?? 2004 Elsevier Ltd. All rights reserved.

  10. HisB as novel selection marker for gene targeting approaches in Aspergillus niger.

    Science.gov (United States)

    Fiedler, Markus R M; Gensheimer, Tarek; Kubisch, Christin; Meyer, Vera

    2017-03-08

    For Aspergillus niger, a broad set of auxotrophic and dominant resistance markers is available. However, only few offer targeted modification of a gene of interest into or at a genomic locus of choice, which hampers functional genomics studies. We thus aimed to extend the available set by generating a histidine auxotrophic strain with a characterized hisB locus for targeted gene integration and deletion in A. niger. A histidine-auxotrophic strain was established via disruption of the A. niger hisB gene by using the counterselectable pyrG marker. After curing, a hisB - , pyrG - strain was obtained, which served as recipient strain for further studies. We show here that both hisB orthologs from A. nidulans and A. niger can be used to reestablish histidine prototrophy in this recipient strain. Whereas the hisB gene from A. nidulans was suitable for efficient gene targeting at different loci in A. niger, the hisB gene from A. niger allowed efficient integration of a Tet-on driven luciferase reporter construct at the endogenous non-functional hisB locus. Subsequent analysis of the luciferase activity revealed that the hisB locus is tight under non-inducing conditions and allows even higher luciferase expression levels compared to the pyrG integration locus. Taken together, we provide here an alternative selection marker for A. niger, hisB, which allows efficient homologous integration rates as well as high expression levels which compare favorably to the well-established pyrG selection marker.

  11. Selective oropharyngeal decontamination versus selective digestive decontamination in critically ill patients: a meta-analysis of randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Zhao D

    2015-07-01

    Full Text Available Di Zhao,1,* Jian Song,2,* Xuan Gao,3 Fei Gao,4 Yupeng Wu,2 Yingying Lu,5 Kai Hou1 1Department of Neurosurgery, The First Hospital of Hebei Medical University, 2Department of Neurosurgery, 3Department of Neurology, The Second Hospital of Hebei Medical University, 4Hebei Provincial Procurement Centers for Medical Drugs and Devices, 5Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang People’s Republic of China *These authors contributed equally to this work Background: Selective digestive decontamination (SDD and selective oropharyngeal decontamination (SOD are associated with reduced mortality and infection rates among patients in intensive care units (ICUs; however, whether SOD has a superior effect than SDD remains uncertain. Hence, we conducted a meta-analysis of randomized controlled trials (RCTs to compare SOD with SDD in terms of clinical outcomes and antimicrobial resistance rates in patients who were critically ill. Methods: RCTs published in PubMed, Embase, and Web of Science were systematically reviewed to compare the effects of SOD and SDD in patients who were critically ill. Outcomes included day-28 mortality, length of ICU stay, length of hospital stay, duration of mechanical ventilation, ICU-acquired bacteremia, and prevalence of antibiotic-resistant Gram-negative bacteria. Results were expressed as risk ratio (RR with 95% confidence intervals (CIs, and weighted mean differences (WMDs with 95% CIs. Pooled estimates were performed using a fixed-effects model or random-effects model, depending on the heterogeneity among studies. Results: A total of four RCTs involving 23,822 patients met the inclusion criteria and were included in this meta-analysis. Among patients whose admitting specialty was surgery, cardiothoracic surgery (57.3% and neurosurgery (29.7% were the two main types of surgery being performed. Pooled results showed that SOD had similar effects as SDD in day-28 mortality (RR =1

  12. Ethnopharmacological versus random plant selection methods for the evaluation of the antimycobacterial activity

    Directory of Open Access Journals (Sweden)

    Danilo R. Oliveira

    2011-05-01

    Full Text Available The municipality of Oriximiná, Brazil, has 33 quilombola communities in remote areas, endowed with wide experience in the use of medicinal plants. An ethnobotanical survey was carried out in five of these communities. A free-listing method directed for the survey of species locally indicated against Tuberculosis and lung problems was also applied. Data were analyzed by quantitative techniques: saliency index and major use agreement. Thirty four informants related 254 ethnospecies. Among these, 43 were surveyed for possible antimycobacterial activity. As a result of those informations, ten species obtained from the ethnodirected approach (ETHNO and eighteen species obtained from the random approach (RANDOM were assayed against Mycobacterium tuberculosis by the microdilution method, using resazurin as an indicator of cell viability. The best results for antimycobacterial activity were obtained of some plants selected by the ethnopharmacological approach (50% ETHNO x 16,7% RANDOM. These results can be even more significant if we consider that the therapeutic success obtained among the quilombola practice is complex, being the use of some plants acting as fortifying agents, depurative, vomitory, purgative and bitter remedy, especially to infectious diseases, of great importance to the communities in the curing or recovering of health as a whole.

  13. FAMACHA©: A potential tool for targeted selective treatment of chronic fasciolosis in sheep.

    Science.gov (United States)

    Olah, Sophie; van Wyk, Jan A; Wall, Richard; Morgan, Eric R

    2015-09-15

    The liver fluke Fasciola hepatica causes considerable damage to the health, welfare and productivity of ruminants in temperate areas, and its control is challenged by anthelmintic resistance. Targeted selective treatment (TST) is an increasingly established strategy for preserving anthelmintic efficacy in grazing livestock, yet no practical indicators are available to target individuals for treatment against fluke infection. This paper evaluates the FAMACHA(©) system, a colour chart for the non-invasive detection of anaemia in small ruminants, for this purpose. FAMACHA(©) scores were collected from 288 sheep prior to slaughter during the winter period, when fluke infections were largely mature, and condemned livers were recovered and adult flukes extracted. Average FAMACHA(©) score was significantly higher (=paler conjunctivae) in animals whose livers were condemned (3.6, n=62) than in those whose livers were not condemned (2.1). The number of adult flukes recovered ranged from 2 to 485, and was positively correlated with FAMACHA(©) score (r(2)=0.54, pFAMACHA(©) score (n=240, r=0.23, pFAMACHA(©) score, and selective treatment of individual sheep with FAMACHA(©) scores above 2 or 3 would have preserved between 27 and 100% of nematodes in refugia on the basis of FEC, depending on group and the threshold used for treatment. FAMACHA(©) holds promise as a tool for selective treatment of sheep against adult F. hepatica, in support of refugia-based control of fluke and nematode infections, and further field evaluation is warranted. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Selective Vitamin D Receptor Activation as Anti-Inflammatory Target in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    J. Donate-Correa

    2014-01-01

    Full Text Available Paricalcitol, a selective vitamin D receptor (VDR activator used for treatment of secondary hyperparathyroidism in chronic kidney disease (CKD, has been associated with survival advantages, suggesting that this drug, beyond its ability to suppress parathyroid hormone, may have additional beneficial actions. In this prospective, nonrandomised, open-label, proof-of-concept study, we evaluated the hypothesis that selective vitamin D receptor activation with paricalcitol is an effective target to modulate inflammation in CKD patients. Eight patients with an estimated glomerular filtration rate between 15 and 44 mL/min/1.73 m2 and an intact parathyroid hormone (PTH level higher than 110 pg/mL received oral paricalcitol (1 μg/48 hours as therapy for secondary hyperparathyroidism. Nine patients matched by age, sex, and stage of CKD, but a PTH level <110 pg/mL, were enrolled as a control group. Our results show that five months of paricalcitol administration were associated with a reduction in serum concentrations of hs-CRP (13.9%, P<0.01, TNF-α (11.9%, P=0.01, and IL-6 (7%, P<0.05, with a nonsignificant increase of IL-10 by 16%. In addition, mRNA expression levels of the TNFα and IL-6 genes in peripheral blood mononuclear cells decreased significantly by 30.8% (P=0.01 and 35.4% (P=0.01, respectively. In conclusion, selective VDR activation is an effective target to modulate inflammation in CKD.

  15. Random forest variable selection in spatial malaria transmission modelling in Mpumalanga Province, South Africa.

    Science.gov (United States)

    Kapwata, Thandi; Gebreslasie, Michael T

    2016-11-16

    Malaria is an environmentally driven disease. In order to quantify the spatial variability of malaria transmission, it is imperative to understand the interactions between environmental variables and malaria epidemiology at a micro-geographic level using a novel statistical approach. The random forest (RF) statistical learning method, a relatively new variable-importance ranking method, measures the variable importance of potentially influential parameters through the percent increase of the mean squared error. As this value increases, so does the relative importance of the associated variable. The principal aim of this study was to create predictive malaria maps generated using the selected variables based on the RF algorithm in the Ehlanzeni District of Mpumalanga Province, South Africa. From the seven environmental variables used [temperature, lag temperature, rainfall, lag rainfall, humidity, altitude, and the normalized difference vegetation index (NDVI)], altitude was identified as the most influential predictor variable due its high selection frequency. It was selected as the top predictor for 4 out of 12 months of the year, followed by NDVI, temperature and lag rainfall, which were each selected twice. The combination of climatic variables that produced the highest prediction accuracy was altitude, NDVI, and temperature. This suggests that these three variables have high predictive capabilities in relation to malaria transmission. Furthermore, it is anticipated that the predictive maps generated from predictions made by the RF algorithm could be used to monitor the progression of malaria and assist in intervention and prevention efforts with respect to malaria.

  16. Random forest variable selection in spatial malaria transmission modelling in Mpumalanga Province, South Africa

    Directory of Open Access Journals (Sweden)

    Thandi Kapwata

    2016-11-01

    Full Text Available Malaria is an environmentally driven disease. In order to quantify the spatial variability of malaria transmission, it is imperative to understand the interactions between environmental variables and malaria epidemiology at a micro-geographic level using a novel statistical approach. The random forest (RF statistical learning method, a relatively new variable-importance ranking method, measures the variable importance of potentially influential parameters through the percent increase of the mean squared error. As this value increases, so does the relative importance of the associated variable. The principal aim of this study was to create predictive malaria maps generated using the selected variables based on the RF algorithm in the Ehlanzeni District of Mpumalanga Province, South Africa. From the seven environmental variables used [temperature, lag temperature, rainfall, lag rainfall, humidity, altitude, and the normalized difference vegetation index (NDVI], altitude was identified as the most influential predictor variable due its high selection frequency. It was selected as the top predictor for 4 out of 12 months of the year, followed by NDVI, temperature and lag rainfall, which were each selected twice. The combination of climatic variables that produced the highest prediction accuracy was altitude, NDVI, and temperature. This suggests that these three variables have high predictive capabilities in relation to malaria transmission. Furthermore, it is anticipated that the predictive maps generated from predictions made by the RF algorithm could be used to monitor the progression of malaria and assist in intervention and prevention efforts with respect to malaria.

  17. Selecting the appropriate pacing mode for patients with sick sinus syndrome: evidence from randomized clinical trials.

    Science.gov (United States)

    Albertsen, A E; Nielsen, J C

    2003-12-01

    Several observational studies have indicated that selection of pacing mode may be important for the clinical outcome in patients with symptomatic bradycardia, affecting the development of atrial fibrillation (AF), thromboembolism, congestive heart failure, mortality and quality of life. In this paper we present and discuss the most recent data from six randomized trials on mode selection in patients with sick sinus syndrome (SSS). In pacing mode selection, VVI(R) pacing is the least attractive solution, increasing the incidence of AF and-as compared with AAI(R) pacing, also the incidence of heart failure, thromboembolism and death. VVI(R) pacing should not be used as the primary pacing mode in patients with SSS, who haven't chronic AF. AAIR pacing is superior to DDDR pacing, reducing AF and preserving left ventricular function. Single site right ventricular pacing-VVI(R) or DDD(R) mode-causes an abnormal ventricular activation and contraction (called ventricular desynchronization), which results in a reduced left ventricular function. Despite the risk of AV block, we consider AAIR pacing to be the optimal pacing mode for isolated SSS today and an algorithm to select patients for AAIR pacing is suggested. Trials on new pacemaker algorithms minimizing right ventricular pacing as well as trials testing alternative pacing sites and multisite pacing to reduce ventricular desynchronization can be expected within the next years.

  18. Geography and genography: prediction of continental origin using randomly selected single nucleotide polymorphisms

    Directory of Open Access Journals (Sweden)

    Ramoni Marco F

    2007-03-01

    Full Text Available Abstract Background Recent studies have shown that when individuals are grouped on the basis of genetic similarity, group membership corresponds closely to continental origin. There has been considerable debate about the implications of these findings in the context of larger debates about race and the extent of genetic variation between groups. Some have argued that clustering according to continental origin demonstrates the existence of significant genetic differences between groups and that these differences may have important implications for differences in health and disease. Others argue that clustering according to continental origin requires the use of large amounts of genetic data or specifically chosen markers and is indicative only of very subtle genetic differences that are unlikely to have biomedical significance. Results We used small numbers of randomly selected single nucleotide polymorphisms (SNPs from the International HapMap Project to train naïve Bayes classifiers for prediction of ancestral continent of origin. Predictive accuracy was tested on two independent data sets. Genetically similar groups should be difficult to distinguish, especially if only a small number of genetic markers are used. The genetic differences between continentally defined groups are sufficiently large that one can accurately predict ancestral continent of origin using only a minute, randomly selected fraction of the genetic variation present in the human genome. Genotype data from only 50 random SNPs was sufficient to predict ancestral continent of origin in our primary test data set with an average accuracy of 95%. Genetic variations informative about ancestry were common and widely distributed throughout the genome. Conclusion Accurate characterization of ancestry is possible using small numbers of randomly selected SNPs. The results presented here show how investigators conducting genetic association studies can use small numbers of arbitrarily

  19. Joint random beam and spectrum selection for spectrum sharing systems with partial channel state information

    KAUST Repository

    Abdallah, Mohamed M.

    2013-11-01

    In this work, we develop joint interference-aware random beam and spectrum selection scheme that provide enhanced performance for the secondary network under the condition that the interference observed at the primary receiver is below a predetermined acceptable value. We consider a secondary link composed of a transmitter equipped with multiple antennas and a single-antenna receiver sharing the same spectrum with a set of primary links composed of a single-antenna transmitter and a single-antenna receiver. The proposed schemes jointly select a beam, among a set of power-optimized random beams, as well as the primary spectrum that maximizes the signal-to-interference-plus-noise ratio (SINR) of the secondary link while satisfying the primary interference constraint. In particular, we consider the case where the interference level is described by a q-bit description of its magnitude, whereby we propose a technique to find the optimal quantizer thresholds in a mean square error (MSE) sense. © 2013 IEEE.

  20. Interference-aware random beam selection schemes for spectrum sharing systems

    KAUST Repository

    Abdallah, Mohamed

    2012-10-19

    Spectrum sharing systems have been recently introduced to alleviate the problem of spectrum scarcity by allowing secondary unlicensed networks to share the spectrum with primary licensed networks under acceptable interference levels to the primary users. In this work, we develop interference-aware random beam selection schemes that provide enhanced performance for the secondary network under the condition that the interference observed by the receivers of the primary network is below a predetermined/acceptable value. We consider a secondary link composed of a transmitter equipped with multiple antennas and a single-antenna receiver sharing the same spectrum with a primary link composed of a single-antenna transmitter and a single-antenna receiver. The proposed schemes select a beam, among a set of power-optimized random beams, that maximizes the signal-to-interference-plus-noise ratio (SINR) of the secondary link while satisfying the primary interference constraint for different levels of feedback information describing the interference level at the primary receiver. For the proposed schemes, we develop a statistical analysis for the SINR statistics as well as the capacity and bit error rate (BER) of the secondary link.

  1. Feature selection for outcome prediction in oesophageal cancer using genetic algorithm and random forest classifier.

    Science.gov (United States)

    Paul, Desbordes; Su, Ruan; Romain, Modzelewski; Sébastien, Vauclin; Pierre, Vera; Isabelle, Gardin

    2017-09-01

    The outcome prediction of patients can greatly help to personalize cancer treatment. A large amount of quantitative features (clinical exams, imaging, …) are potentially useful to assess the patient outcome. The challenge is to choose the most predictive subset of features. In this paper, we propose a new feature selection strategy called GARF (genetic algorithm based on random forest) extracted from positron emission tomography (PET) images and clinical data. The most relevant features, predictive of the therapeutic response or which are prognoses of the patient survival 3 years after the end of treatment, were selected using GARF on a cohort of 65 patients with a local advanced oesophageal cancer eligible for chemo-radiation therapy. The most relevant predictive results were obtained with a subset of 9 features leading to a random forest misclassification rate of 18±4% and an areas under the of receiver operating characteristic (ROC) curves (AUC) of 0.823±0.032. The most relevant prognostic results were obtained with 8 features leading to an error rate of 20±7% and an AUC of 0.750±0.108. Both predictive and prognostic results show better performances using GARF than using 4 other studied methods. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Targeted Curing of All Lysogenic Bacteriophage from Streptococcus pyogenes Using a Novel Counter-selection Technique.

    Science.gov (United States)

    Euler, Chad W; Juncosa, Barbara; Ryan, Patricia A; Deutsch, Douglas R; McShan, W Michael; Fischetti, Vincent A

    2016-01-01

    Streptococcus pyogenes is a human commensal and a bacterial pathogen responsible for a wide variety of human diseases differing in symptoms, severity, and tissue tropism. The completed genome sequences of >37 strains of S. pyogenes, representing diverse disease-causing serotypes, have been published. The greatest genetic variation among these strains is attributed to numerous integrated prophage and prophage-like elements, encoding several virulence factors. A comparison of isogenic strains, differing in prophage content, would reveal the effects of these elements on streptococcal pathogenesis. However, curing strains of prophage is often difficult and sometimes unattainable. We have applied a novel counter-selection approach to identify rare S. pyogenes mutants spontaneously cured of select prophage. To accomplish this, we first inserted a two-gene cassette containing a gene for kanamycin resistance (KanR) and the rpsL wild-type gene, responsible for dominant streptomycin sensitivity (SmS), into a targeted prophage on the chromosome of a streptomycin resistant (SmR) mutant of S. pyogenes strain SF370. We then applied antibiotic counter-selection for the re-establishment of the KanS/SmR phenotype to select for isolates cured of targeted prophage. This methodology allowed for the precise selection of spontaneous phage loss and restoration of the natural phage attB attachment sites for all four prophage-like elements in this S. pyogenes chromosome. Overall, 15 mutants were constructed that encompassed every permutation of phage knockout as well as a mutant strain, named CEM1ΔΦ, completely cured of all bacteriophage elements (a ~10% loss of the genome); the only reported S. pyogenes strain free of prophage-like elements. We compared CEM1ΔΦ to the WT strain by analyzing differences in secreted DNase activity, as well as lytic and lysogenic potential. These mutant strains should allow for the direct examination of bacteriophage relationships within S. pyogenes and

  3. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology.

    Science.gov (United States)

    Galdeano, Carles; Ciulli, Alessio

    2016-09-01

    Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity.

  4. High-Target vs Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients - A Randomized Controlled Trial

    DEFF Research Database (Denmark)

    Vedel, Anne G; Holmgaard, Frederik; Rasmussen, Lars S

    2018-01-01

    % of patients. It is unclear if a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. Methods -In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70-80 mmHg) or lower (40-50 mmHg) target for mean arterial pressure...... by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L/min/m2. The primary outcome was the total volume of new ischemic cerebral lesions (sum in mm3), expressed as the difference between DWI conducted preoperatively and again postoperatively between day 3 and 6. Secondary...

  5. A framework for the targeted selection of herbs with similar efficacy by exploiting drug repositioning technique and curated biomedical knowledge.

    Science.gov (United States)

    Yea, Sang-Jun; Kim, Bu-Yeo; Kim, Chul; Yi, Mun Yong

    2017-08-17

    Plants have been the most important natural resources for traditional medicine and for the modern pharmaceutical industry. They have been in demand in regards to finding alternative medicinal herbs with similar efficacy. Due to the very low probability of discovering useful compounds by random screening, researchers have advocated for using targeted selection approaches. Furthermore, because drug repositioning can speed up the process of drug development, an integrated technique that exploits chemical, genetic, and disease information has been recently developed. Building upon these findings, in this paper, we propose a novel framework for the targeted selection of herbs with similar efficacy by exploiting drug repositioning technique and curated modern scientific biomedical knowledge, with the goal of improving the possibility of inferring the traditional empirical ethno-pharmacological knowledge. To rank candidate herbs on the basis of similarities against target herb, we proposed and evaluated a framework that is comprised of the following four layers: links, extract, similarity, and model. In the framework, multiple databases are linked to build an herb-compound-protein-disease network which was composed of one tripartite network and two bipartite networks allowing comprehensive and detailed information to be extracted. Further, various similarity scores between herbs are calculated, and then prediction models are trained and tested on the basis of theses similarity features. The proposed framework has been found to be feasible in terms of link loss. Out of the 50 similarities, the best one enhanced the performance of ranking herbs with similar efficacy by about 120-320% compared with our previous study. Also, the prediction model showed improved performance by about 180-480%. While building the prediction model, we identified the compound information as being the most important knowledge source and structural similarity as the most useful measure. In the

  6. CarPrice versus CarpRice: Word Boundary Ambiguity Influences Saccade Target Selection during the Reading of Chinese Sentences

    Science.gov (United States)

    Yan, Ming; Kliegl, Reinhold

    2016-01-01

    As a contribution to a theoretical debate about the degree of high-level influences on saccade targeting during sentence reading, we investigated eye movements during the reading of structurally ambiguous Chinese character strings and examined whether parafoveal word segmentation could influence saccade-target selection. As expected, ambiguous…

  7. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

    Science.gov (United States)

    Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L; Hansen, T Matt; Risi, Roberto M; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G; Martin, Ruth L; Torrent, Maricel; Chiang, Gary G; Karukurichi, Kannan; Langston, J William; Weinert, Brian T; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A; Rosenberg, Saul H; Michaelides, Michael R; Lai, Albert; Bromberg, Kenneth D

    2017-10-05

    The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

  8. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    Energy Technology Data Exchange (ETDEWEB)

    Lasko, Loren M.; Jakob, Clarissa G.; Edalji, Rohinton P.; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L.; Hansen, T. Matt; Risi, Roberto M.; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T.; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G.; Martin, Ruth L.; Torrent, Maricel; Chiang, Gary G.; Karukurichi, Kannan; Langston, J. William; Weinert, Brian T.; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H.; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A.; Rosenberg, Saul H.; Michaelides, Michael R.; Lai, Albert; Bromberg, Kenneth D.

    2017-09-27

    The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

  9. Metaproteomics-guided selection of targeted enzymes for bioprospecting of mixed microbial communities.

    Science.gov (United States)

    Speda, Jutta; Jonsson, Bengt-Harald; Carlsson, Uno; Karlsson, Martin

    2017-01-01

    Hitherto, the main goal of metaproteomic analyses has been to characterize the functional role of particular microorganisms in the microbial ecology of various microbial communities. Recently, it has been suggested that metaproteomics could be used for bioprospecting microbial communities to query for the most active enzymes to improve the selection process of industrially relevant enzymes. In the present study, to reduce the complexity of metaproteomic samples for targeted bioprospecting of novel enzymes, a microbial community capable of producing cellulases was maintained on a chemically defined medium in an enzyme suppressed metabolic steady state. From this state, it was possible to specifically and distinctively induce the desired cellulolytic activity. The extracellular fraction of the protein complement of the induced sample could thereby be purified and compared to a non-induced sample of the same community by differential gel electrophoresis to discriminate between constitutively expressed proteins and proteins upregulated in response to the inducing substance. Using the applied approach, downstream analysis by mass spectrometry could be limited to only proteins recognized as upregulated in the cellulase-induced sample. Of 39 selected proteins, the majority were found to be linked to the need to degrade, take up, and metabolize cellulose. In addition, 28 (72%) of the proteins were non-cytosolic and 17 (44%) were annotated as carbohydrate-active enzymes. The results demonstrated both the applicability of the proposed approach for identifying extracellular proteins and guiding the selection of proteins toward those specifically upregulated and targeted by the enzyme inducing substance. Further, because identification of interesting proteins was based on the regulation of enzyme expression in response to a need to hydrolyze and utilize a specific substance, other unexpected enzyme activities were able to be identified. The described approach created the

  10. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    Directory of Open Access Journals (Sweden)

    Joana R. Viola

    2013-01-01

    Full Text Available Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed.

  11. Antibody Selection for Cancer Target Validation of FSH-Receptor in Immunohistochemical Settings

    Directory of Open Access Journals (Sweden)

    Nina Moeker

    2017-10-01

    Full Text Available Background: The follicle-stimulating hormone (FSH-receptor (FSHR has been reported to be an attractive target for antibody therapy in human cancer. However, divergent immunohistochemical (IHC findings have been reported for FSHR expression in tumor tissues, which could be due to the specificity of the antibodies used. Methods: Three frequently used antibodies (sc-7798, sc-13935, and FSHR323 were validated for their suitability in an immunohistochemical study for FSHR expression in different tissues. As quality control, two potential therapeutic anti-hFSHR Ylanthia® antibodies (Y010913, Y010916 were used. The specificity criteria for selection of antibodies were binding to native hFSHR of different sources, and no binding to non-related proteins. The ability of antibodies to stain the paraffin-embedded Flp-In Chinese hamster ovary (CHO/FSHR cells was tested after application of different epitope retrieval methods. Results: From the five tested anti-hFSHR antibodies, only Y010913, Y010916, and FSHR323 showed specific binding to native, cell-presented hFSHR. Since Ylanthia® antibodies were selected to specifically recognize native FSHR, as required for a potential therapeutic antibody candidate, FSHR323 was the only antibody to detect the receptor in IHC/histochemical settings on transfected cells, and at markedly lower, physiological concentrations (ex., in Sertoli cells of human testes. The pattern of FSH323 staining noticed for ovarian, prostatic, and renal adenocarcinomas indicated that FSHR was expressed mainly in the peripheral tumor blood vessels. Conclusion: Of all published IHC antibodies tested, only antibody FSHR323 proved suitable for target validation of hFSHR in an IHC setting for cancer. Our studies could not confirm the previously reported FSHR overexpression in ovarian and prostate cancer cells. Instead, specific overexpression in peripheral tumor blood vessels could be confirmed after thorough validation of the antibodies used.

  12. Selective targeting of gain-of-function KCNQ1 mutations predisposing to atrial fibrillation.

    Science.gov (United States)

    Campbell, Courtney M; Campbell, Jonathan D; Thompson, Christopher H; Galimberti, Eleonora Savio; Darbar, Dawood; Vanoye, Carlos G; George, Alfred L

    2013-10-01

    Atrial fibrillation is the most common sustained cardiac arrhythmia in adults. We hypothesized that gain-of-function KCNQ1 mutations previously associated with familial atrial fibrillation have distinct pharmacological properties that may enable targeted inhibition. Wild-type (WT) KCNQ1 or the familial atrial fibrillation mutation KCNQ1-S140G was heterologously coexpressed with KCNE1 to enable electrophysiological recording of the slow delayed rectifier current (IKs) and investigation of pharmacological effects of the IKs selective blocker HMR-1556. Coexpression of KCNQ1-S140G with KCNE1 generated potassium currents (S140G-IKs) that exhibited greater sensitivity to HMR-1556 than WT-IKs. Enhanced HMR-1556 sensitivity was also observed for another gain-of-function atrial fibrillation mutation, KCNQ1-V141M. Heteromeric expression of KCNE1 with both KCNQ1-WT and KCNQ1-S140G generated currents (HET-IKs) with gain-of-function features, including larger amplitude, a constitutively active component, hyperpolarized voltage dependence of activation, and extremely slow deactivation. A low concentration of HMR-1556, which had little effect on WT-IKs but was capable of inhibiting the mutant channel, reduced both instantaneous and steady state HET-IKs to levels that were not significantly different from WT-IKs and attenuated use-dependent accumulation of the current. In cultured adult rabbit left atrial myocytes, expression of S140G-IKs shortened action potential duration compared with WT-IKs. Application of HMR-1556 mitigated S140G-IKs-induced action potential duration shortening and did not alter action potential duration in cells expressing WT-IKs. The enhanced sensitivity of KCNQ1 gain-of-function mutations for HMR-1556 suggests the possibility of selective therapeutic targeting, and, therefore, our data illustrate a potential proof of principle for genotype-specific treatment of this heritable arrhythmia.

  13. Parieto-occipital cortex shows early target selection to faces in a reflexive orienting task.

    Science.gov (United States)

    Morand, Stéphanie M; Harvey, Monika; Grosbras, Marie-Hélène

    2014-04-01

    It is well established that human faces induce stronger involuntary orienting responses than other visual objects. Yet, the timing of this preferential orienting response at the neural level is still unknown. Here, we used an antisaccade paradigm to investigate the neural dynamics preceding the onset of reflexive and voluntary saccades elicited by human faces and nonface visual objects, normalized for their global low-level visual properties. High-density event-related potentials (ERPs) were recorded in observers as they performed interleaved pro- and antisaccades toward a lateralized target. For reflexive saccades, we report an ERP modulation specific to faces as early as 40-60 ms following stimulus onset over parieto-occipital sites, further predicting the speed of saccade execution. This was not linked to differences in the programming of the saccadic eye movements, as it occurred early in time. For the first time, we present electrophysiological evidence of early target selection to faces in reflexive orienting responses over parieto-occipital cortex that facilitates the triggering of saccades toward faces. We argue for a 2-stage process in the representation of a face in involuntary spatial orienting with an initial, rapid implicit processing of the visual properties of a face, followed by subsequent stimulus categorization depicted by the N170 component.

  14. Searching for life on Mars: selection of molecular targets for ESA's aurora ExoMars mission.

    Science.gov (United States)

    Parnell, John; Cullen, David; Sims, Mark R; Bowden, Stephen; Cockell, Charles S; Court, Richard; Ehrenfreund, Pascale; Gaubert, Francois; Grant, William; Parro, Victor; Rohmer, Michel; Sephton, Mark; Stan-Lotter, Helga; Steele, Andrew; Toporski, Jan; Vago, Jorge

    2007-08-01

    The European Space Agency's ExoMars mission will seek evidence of organic compounds of biological and non-biological origin at the martian surface. One of the instruments in the Pasteur payload may be a Life Marker Chip that utilizes an immunoassay approach to detect specific organic molecules or classes of molecules. Therefore, it is necessary to define and prioritize specific molecular targets for antibody development. Target compounds have been selected to represent meteoritic input, fossil organic matter, extant (living, recently dead) organic matter, and contamination. Once organic molecules are detected on Mars, further information is likely to derive from the detailed distribution of compounds rather than from single molecular identification. This will include concentration gradients beneath the surface and gradients from generic to specific compounds. The choice of biomarkers is informed by terrestrial biology but is wide ranging, and nonterrestrial biology may be evident from unexpected molecular distributions. One of the most important requirements is to sample where irradiation and oxidation are minimized, either by drilling or by using naturally excavated exposures. Analyzing regolith samples will allow for the search of both extant and fossil biomarkers, but sequential extraction would be required to optimize the analysis of each of these in turn.

  15. In vitro selection of a DNA aptamer targeted against Shigella dysenteriae.

    Science.gov (United States)

    Duan, Nuo; Ding, Xiaoying; Wu, Shijia; Xia, Yu; Ma, Xiaoyuan; Wang, Zhouping; Chen, Jie

    2013-09-01

    To identify DNA aptamers demonstrating binding specificity for Shigella dysenteriae, a whole-bacterium Systemic Evolution of Ligands by Exponential enrichment (SELEX) method was applied to a combinatorial library of single-stranded DNA (ssDNA) molecules. After several rounds of selection using S. dysenteriae as the target, the highly enriched oligonucleotide pool was sequenced and then grouped into different families based on primary sequence homologies and similarities in the secondary structures. Aptamer S 1, which showed particularly high binding affinity in preliminary studies, was chosen for further characterisation. This aptamer displayed a dissociation constant (Kd value) of 23.47 ± 2.48 nM. Binding assays to assess the specificity of aptamer S 1 showed high binding affinity for S. dysenteriae and low apparent binding affinity for other bacteria. The ssDNA aptamers generated may serve as a new type of molecular probe for microbial pathogens, as it has the potential to overcome the tedious isolation and purification requirements for complex targets. © 2013.

  16. Non-invasive brain stimulation targeting the right fusiform gyrus selectively increases working memory for faces.

    Science.gov (United States)

    Brunyé, Tad T; Moran, Joseph M; Holmes, Amanda; Mahoney, Caroline R; Taylor, Holly A

    2017-04-01

    The human extrastriate cortex contains a region critically involved in face detection and memory, the right fusiform gyrus. The present study evaluated whether transcranial direct current stimulation (tDCS) targeting this anatomical region would selectively influence memory for faces versus non-face objects (houses). Anodal tDCS targeted the right fusiform gyrus (Brodmann's Area 37), with the anode at electrode site PO10, and cathode at FP2. Two stimulation conditions were compared in a repeated-measures design: 0.5mA versus 1.5mA intensity; a separate control group received no stimulation. Participants completed a working memory task for face and house stimuli, varying in memory load from 1 to 4 items. Individual differences measures assessed trait-based differences in facial recognition skills. Results showed 1.5mA intensity stimulation (versus 0.5mA and control) increased performance at high memory loads, but only with faces. Lower overall working memory capacity predicted a positive impact of tDCS. Results provide support for the notion of functional specialization of the right fusiform regions for maintaining face (but not non-face object) stimuli in working memory, and further suggest that low intensity electrical stimulation of this region may enhance demanding face working memory performance particularly in those with relatively poor baseline working memory skills. Published by Elsevier Inc.

  17. Target selection and annotation for the structural genomics of the amidohydrolase and enolase superfamilies.

    Science.gov (United States)

    Pieper, Ursula; Chiang, Ranyee; Seffernick, Jennifer J; Brown, Shoshana D; Glasner, Margaret E; Kelly, Libusha; Eswar, Narayanan; Sauder, J Michael; Bonanno, Jeffrey B; Swaminathan, Subramanyam; Burley, Stephen K; Zheng, Xiaojing; Chance, Mark R; Almo, Steven C; Gerlt, John A; Raushel, Frank M; Jacobson, Matthew P; Babbitt, Patricia C; Sali, Andrej

    2009-04-01

    To study the substrate specificity of enzymes, we use the amidohydrolase and enolase superfamilies as model systems; members of these superfamilies share a common TIM barrel fold and catalyze a wide range of chemical reactions. Here, we describe a collaboration between the Enzyme Specificity Consortium (ENSPEC) and the New York SGX Research Center for Structural Genomics (NYSGXRC) that aims to maximize the structural coverage of the amidohydrolase and enolase superfamilies. Using sequence- and structure-based protein comparisons, we first selected 535 target proteins from a variety of genomes for high-throughput structure determination by X-ray crystallography; 63 of these targets were not previously annotated as superfamily members. To date, 20 unique amidohydrolase and 41 unique enolase structures have been determined, increasing the fraction of sequences in the two superfamilies that can be modeled based on at least 30% sequence identity from 45% to 73%. We present case studies of proteins related to uronate isomerase (an amidohydrolase superfamily member) and mandelate racemase (an enolase superfamily member), to illustrate how this structure-focused approach can be used to generate hypotheses about sequence-structure-function relationships.

  18. The Breakthrough Listen Search for Intelligent Life: Target Selection of Nearby Stars and Galaxies

    Science.gov (United States)

    Isaacson, Howard; Siemion, Andrew P. V.; Marcy, Geoffrey W.; Lebofsky, Matt; Price, Danny C.; MacMahon, David; Croft, Steve; DeBoer, David; Hickish, Jack; Werthimer, Dan; Sheikh, Sofia; Hellbourg, Greg; Enriquez, J. Emilio

    2017-05-01

    We present the target selection for the Breakthrough Listen search for extraterrestrial intelligence during the first year of observations at the Green Bank Telescope, Parkes Telescope, and Automated Planet Finder. On the way to observing 1,000,000 nearby stars in search of technological signals, we present three main sets of objects we plan to observe in addition to a smaller sample of exotica. We chose the 60 nearest stars, all within 5.1 pc from the Sun. Such nearby stars offer the potential to observe faint radio signals from transmitters that have a power similar to those on Earth. We add a list of 1649 stars drawn from the Hipparcos catalog that span the Hertzprung-Russell diagram, including all spectral types along the main sequence, subgiants, and giant stars. This sample offers diversity and inclusion of all stellar types, but with thoughtful limits and due attention to main sequence stars. Our targets also include 123 nearby galaxies composed of a “morphological-type-complete” sample of the nearest spirals, ellipticals, dwarf spherioidals, and irregulars. While their great distances hamper the detection of technological electromagnetic radiation, galaxies offer the opportunity to observe billions of stars simultaneously and to sample the bright end of the technological luminosity function. We will also use the Green Bank and Parkes telescopes to survey the plane and central bulge of the Milky Way. Finally, the complete target list includes several classes of exotica, including white dwarfs, brown dwarfs, black holes, neutron stars, and asteroids in our solar system.

  19. Does the Use of a Decision Aid Improve Decision Making in Prosthetic Heart Valve Selection? A Multicenter Randomized Trial

    NARCIS (Netherlands)

    Korteland, Nelleke M.; Ahmed, Yunus; Koolbergen, David R.; Brouwer, Marjan; de Heer, Frederiek; Kluin, Jolanda; Bruggemans, Eline F.; Klautz, Robert J. M.; Stiggelbout, Anne M.; Bucx, Jeroen J. J.; Roos-Hesselink, Jolien W.; Polak, Peter; Markou, Thanasie; van den Broek, Inge; Ligthart, Rene; Bogers, Ad J. J. C.; Takkenberg, Johanna J. M.

    2017-01-01

    A Dutch online patient decision aid to support prosthetic heart valve selection was recently developed. A multicenter randomized controlled trial was conducted to assess whether use of the patient decision aid results in optimization of shared decision making in prosthetic heart valve selection. In

  20. Selective outcome reporting and sponsorship in randomized controlled trials in IVF and ICSI.

    Science.gov (United States)

    Braakhekke, M; Scholten, I; Mol, F; Limpens, J; Mol, B W; van der Veen, F

    2017-10-01

    Are randomized controlled trials (RCTs) on IVF and ICSI subject to selective outcome reporting and is this related to sponsorship? There are inconsistencies, independent from sponsorship, in the reporting of primary outcome measures in the majority of IVF and ICSI trials, indicating selective outcome reporting. RCTs are subject to bias at various levels. Of these biases, selective outcome reporting is particularly relevant to IVF and ICSI trials since there is a wide variety of outcome measures to choose from. An established cause of reporting bias is sponsorship. It is, at present, unknown whether RCTs in IVF/ICSI are subject to selective outcome reporting and whether this is related with sponsorship. We systematically searched RCTs on IVF and ICSI published between January 2009 and March 2016 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the publisher subset of PubMed. We analysed 415 RCTs. Per included RCT, we extracted data on impact factor of the journal, sample size, power calculation, and trial registry and thereafter data on primary outcome measure, the direction of trial results and sponsorship. Of the 415 identified RCTs, 235 were excluded for our primary analysis, because the sponsorship was not reported. Of the 180 RCTs included in our analysis, 7 trials did not report on any primary outcome measure and 107 of the remaining 173 trials (62%) reported on surrogate primary outcome measures. Of the 114 registered trials, 21 trials (18%) provided primary outcomes in their manuscript that were different from those in the trial registry. This indicates selective outcome reporting. We found no association between selective outcome reporting and sponsorship. We ran additional analyses to include the trials that had not reported sponsorship and found no outcomes that differed from our primary analysis. Since the majority of the trials did not report on sponsorship, there is a risk on sampling bias. IVF and ICSI trials are subject, to

  1. High-Target vs Low-Target Blood Pressure Management During Cardiopulmonary Bypass to Prevent Cerebral Injury in Cardiac Surgery Patients - A Randomized Controlled Trial.

    Science.gov (United States)

    Vedel, Anne G; Holmgaard, Frederik; Rasmussen, Lars S; Langkilde, Annika; Paulson, Olaf B; Lange, Theis; Thomsen, Carsten; Olsen, Peter Skov; Ravn, Hanne Berg; Nilsson, Jens C

    2018-01-16

    Background -Cerebral injury is an important complication following cardiac surgery with the use of cardiopulmonary bypass (CPB). The rate of overt stroke after cardiac surgery is 1-2%, whereas silent strokes, detected by diffusion-weighed magnetic resonance imaging (DWI), are found in up to 50% of patients. It is unclear if a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. Methods -In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70-80 mmHg) or lower (40-50 mmHg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L/min/m2. The primary outcome was the total volume of new ischemic cerebral lesions (sum in mm3), expressed as the difference between DWI conducted preoperatively and again postoperatively between day 3 and 6. Secondary outcomes included DWI-evaluated total number of new ischemic lesions. Results -Among the 197 enrolled patients, mean (SD) age was 65.0 (10.7) years in the low-target group (n=99) and 69.4 (8.9) years in the high-target group (n=98). Procedural risk scores were comparable between groups. Overall, DWI revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group (p = 0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm3 (interquartile range [IQR], 0-118; range 0-25261) in the low-target group vs 29 mm3 (IQR 0-143; range 0-22116) in the high-target group (median difference estimate, 0 (95% confidence interval [95% CI] -25 - 0.028); P=0.99), as was the secondary outcome of number of new lesions (1 (IQR 0-2; range 0-24) vs 1 (IQR 0-2; range 0-29) respectively; median difference estimate, 0 (95% CI 0 - 0); P=0.71). No significant difference was observed in frequency of severe adverse events. Conclusions -Among patients undergoing on-pump cardiac surgery, targeting a higher

  2. Specific and selective probes for Staphylococcus aureus from phage-displayed random peptide libraries.

    Science.gov (United States)

    De Plano, Laura M; Carnazza, Santina; Messina, Grazia M L; Rizzo, Maria Giovanna; Marletta, Giovanni; Guglielmino, Salvatore P P

    2017-09-01

    Staphylococcus aureus is a major human pathogen causing health care-associated and community-associated infections. Early diagnosis is essential to prevent disease progression and to reduce complications that can be serious. In this study, we selected, from a 9-mer phage peptide library, a phage clone displaying peptide capable of specific binding to S. aureus cell surface, namely St.au9IVS5 (sequence peptide RVRSAPSSS).The ability of the isolated phage clone to interact specifically with S. aureus and the efficacy of its bacteria-binding properties were established by using enzyme linked immune-sorbent assay (ELISA). We also demonstrated by Western blot analysis that the most reactive and selective phage peptide binds a 78KDa protein on the bacterial cell surface. Furthermore, we observed selectivity of phage-bacteria-binding allowing to identify clinical isolates of S. aureus in comparison with a panel of other bacterial species. In order to explore the possibility of realizing a selective bacteria biosensor device, based on immobilization of affinity-selected phage, we have studied the physisorbed phage deposition onto a mica surface. Atomic Force Microscopy (AFM) was used to determine the organization of phage on mica surface and then the binding performance of mica-physisorbed phage to bacterial target was evaluated during the time by fluorescent microscopy. The system is able to bind specifically about 50% of S. aureus cells after 15' and 90% after one hour. Due to specificity and rapidness, this biosensing strategy paves the way to the further development of new cheap biosensors to be used in developing countries, as lab-on-chip (LOC) to detect bacterial agents in clinical diagnostics applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Improving Recognition of Antimicrobial Peptides and Target Selectivity through Machine Learning and Genetic Programming.

    Science.gov (United States)

    Veltri, Daniel; Kamath, Uday; Shehu, Amarda

    2017-01-01

    Growing bacterial resistance to antibiotics is spurring research on utilizing naturally-occurring antimicrobial peptides (AMPs) as templates for novel drug design. While experimentalists mainly focus on systematic point mutations to measure the effect on antibacterial activity, the computational community seeks to understand what determines such activity in a machine learning setting. The latter seeks to identify the biological signals or features that govern activity. In this paper, we advance research in this direction through a novel method that constructs and selects complex sequence-based features which capture information about distal patterns within a peptide. Comparative analysis with state-of-the-art methods in AMP recognition reveals our method is not only among the top performers, but it also provides transparent summarizations of antibacterial activity at the sequence level. Moreover, this paper demonstrates for the first time the capability not only to recognize that a peptide is an AMP or not but also to predict its target selectivity based on models of activity against only Gram-positive, only Gram-negative, or both types of bacteria. The work described in this paper is a step forward in computational research seeking to facilitate AMP design or modification in the wet laboratory.

  4. Identifying Human Genome-Wide CNV, LOH and UPD by Targeted Sequencing of Selected Regions.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Copy-number variations (CNV, loss of heterozygosity (LOH, and uniparental disomy (UPD are large genomic aberrations leading to many common inherited diseases, cancers, and other complex diseases. An integrated tool to identify these aberrations is essential in understanding diseases and in designing clinical interventions. Previous discovery methods based on whole-genome sequencing (WGS require very high depth of coverage on the whole genome scale, and are cost-wise inefficient. Another approach, whole exome genome sequencing (WEGS, is limited to discovering variations within exons. Thus, we are lacking efficient methods to detect genomic aberrations on the whole genome scale using next-generation sequencing technology. Here we present a method to identify genome-wide CNV, LOH and UPD for the human genome via selectively sequencing a small portion of genome termed Selected Target Regions (SeTRs. In our experiments, the SeTRs are covered by 99.73%~99.95% with sufficient depth. Our developed bioinformatics pipeline calls genome-wide CNVs with high confidence, revealing 8 credible events of LOH and 3 UPD events larger than 5M from 15 individual samples. We demonstrate that genome-wide CNV, LOH and UPD can be detected using a cost-effective SeTRs sequencing approach, and that LOH and UPD can be identified using just a sample grouping technique, without using a matched sample or familial information.

  5. Fast and behavior-selective exploitation of a marine fish targeted by anglers

    Science.gov (United States)

    Alós, Josep; Palmer, Miquel; Rosselló, Rosario; Arlinghaus, Robert

    2016-12-01

    Harvesting of wild-living animals is often intensive and may selectively target heritable behavioral traits. We studied the exploitation dynamics and the vulnerability consequences of individual heterogeneity in movement-related behaviors in free-ranging pearly razorfish (Xyrichthys novacula). Using underwater-video recording, we firstly document a fast and high exploitation rate of about 60% of the adult population removed in just few days after the opening of the season. Subsequently, we tagged a sample of individuals with acoustic transmitters and studied whether behavioral traits were significant predictors of the vulnerability to angling. Tagged individuals revealed repeatable behaviors in several home range-related traits, suggesting the presence of spatial behavioral types. The individuals surviving the experimental fishery showed only localized and low-intensity movement patterns. Our study provides new insights for understanding the harvesting pressures and selective properties acting on behavioral traits of recreational fishing. Many fish stocks around the globe are today predominantly exploited by recreational fisheries. The fisheries-induced change in fish behavior described here may be therefore widespread, and has the potential to alter food-webs, profitability of the fisheries and to affect stock assessment by eroding catchability in the long-term.

  6. Active classifier selection for RGB-D object categorization using a Markov random field ensemble method

    Science.gov (United States)

    Durner, Maximilian; Márton, Zoltán.; Hillenbrand, Ulrich; Ali, Haider; Kleinsteuber, Martin

    2017-03-01

    In this work, a new ensemble method for the task of category recognition in different environments is presented. The focus is on service robotic perception in an open environment, where the robot's task is to recognize previously unseen objects of predefined categories, based on training on a public dataset. We propose an ensemble learning approach to be able to flexibly combine complementary sources of information (different state-of-the-art descriptors computed on color and depth images), based on a Markov Random Field (MRF). By exploiting its specific characteristics, the MRF ensemble method can also be executed as a Dynamic Classifier Selection (DCS) system. In the experiments, the committee- and topology-dependent performance boost of our ensemble is shown. Despite reduced computational costs and using less information, our strategy performs on the same level as common ensemble approaches. Finally, the impact of large differences between datasets is analyzed.

  7. Identification of genomic variants putatively targeted by selection during dog domestication.

    Science.gov (United States)

    Cagan, Alex; Blass, Torsten

    2016-01-12

    Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight-or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest

  8. Clinical outcome of intracytoplasmic injection of spermatozoa morphologically selected under high magnification: a prospective randomized study.

    Science.gov (United States)

    Balaban, Basak; Yakin, Kayhan; Alatas, Cengiz; Oktem, Ozgur; Isiklar, Aycan; Urman, Bulent

    2011-05-01

    Recent evidence shows that the selection of spermatozoa based on the analysis of morphology under high magnification (×6000) may have a positive impact on embryo development in cases with severe male factor infertility and/or previous implantation failures. The objective of this prospective randomized study was to compare the clinical outcome of 87 intracytoplasmic morphologically selected sperm injection (IMSI) cycles with 81 conventional intracytoplasmic sperm injection (ICSI) cycles in an unselected infertile population. IMSI did not provide a significant improvement in the clinical outcome compared with ICSI although there were trends for higher implantation (28.9% versus 19.5%), clinical pregnancy (54.0% versus 44.4%) and live birth rates (43.7% versus 38.3%) in the IMSI group. However, severe male factor patients benefited from the IMSI procedure as shown by significantly higher implantation rates compared with their counterparts in the ICSI group (29.6% versus 15.2%, P=0.01). These results suggest that IMSI may improve IVF success rates in a selected group of patients with male factor infertility. New technological developments enable the real time examination of motile spermatozoa with an inverted light microscope equipped with high-power differential interference contrast optics, enhanced by digital imaging. High magnification (over ×6000) provides the identification of spermatozoa with a normal nucleus and nuclear content. Intracytoplasmic injection of spermatozoa selected according to fine nuclear morphology under high magnification may improve the clinical outcome in cases with severe male factor infertility. Copyright © 2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  9. A Comparison of Dietary Habits between Recreational Runners and a Randomly Selected Adult Population in Slovenia.

    Science.gov (United States)

    Škof, Branko; Rotovnik Kozjek, Nada

    2015-09-01

    The aim of the study was to compare the dietary habits of recreational runners with those of a random sample of the general population. We also wanted to determine the influence of gender, age and sports performance of recreational runners on their basic diet and compliance with recommendations in sports nutrition. The study population consisted of 1,212 adult Slovenian recreational runners and 774 randomly selected residents of Slovenia between the ages of 18 and 65 years. The data on the dietary habits of our subjects was gathered by means of two questionnaires. The following parameters were evaluated: the type of diet, a food pattern, and the frequency of consumption of individual food groups, the use of dietary supplements, fluid intake, and alcohol consumption. Recreational runners had better compliance with recommendations for healthy nutrition than the general population. This pattern increased with the runner's age and performance level. Compared to male runners, female runners ate more regularly and had a more frequent consumption of food groups associated with a healthy diet (fruit, vegetables, whole grain foods, and low-fat dairy products). The consumption of simple sugars and use of nutritional supplements by well-trained runners was inadequate with values recommended for physically active individuals. Recreational runners are an exemplary population group that actively seeks to adopt a healthier lifestyle.

  10. Radiographic methods used before removal of mandibular third molars among randomly selected general dental clinics.

    Science.gov (United States)

    Matzen, Louise H; Petersen, Lars B; Wenzel, Ann

    2016-01-01

    To assess radiographic methods and diagnostically sufficient images used before removal of mandibular third molars among randomly selected general dental clinics. Furthermore, to assess factors predisposing for an additional radiographic examination. 2 observers visited 18 randomly selected clinics in Denmark and studied patient files, including radiographs of patients who had their mandibular third molar(s) removed. The radiographic unit and type of receptor were registered. A diagnostically sufficient image was defined as the whole tooth and mandibular canal were displayed in the radiograph (yes/no). Overprojection between the tooth and mandibular canal (yes/no) and patient-reported inferior alveolar nerve sensory disturbances (yes/no) were recorded. Regression analyses tested if overprojection between the third molar and the mandibular canal and an insufficient intraoral image predisposed for additional radiographic examination(s). 1500 mandibular third molars had been removed; 1090 had intraoral, 468 had panoramic and 67 had CBCT examination. 1000 teeth were removed after an intraoral examination alone, 433 after panoramic examination and 67 after CBCT examination. 90 teeth had an additional examination after intraoral. Overprojection between the tooth and mandibular canal was a significant factor (p < 0.001, odds ratio = 3.56) for an additional examination. 63.7% of the intraoral images were sufficient and 36.3% were insufficient, with no significant difference between images performed with phosphor plates and solid-state sensors (p = 0.6). An insufficient image predisposed for an additional examination (p = 0.008, odds ratio = 1.8) but was only performed in 11% of the cases. Most mandibular third molars were removed based on an intraoral examination although 36.3% were insufficient.

  11. In vitro selection of external guide sequences for directing human RNase P to cleave a target mRNA.

    Science.gov (United States)

    Raj, Stephen; Liu, Fenyong

    2004-01-01

    External guide sequences (EGSs) are oligonucleotides that consist of a sequence that is complementary to a target mRNA and recruit intracellular RNase P for specific degradation of the target RNA. Recent studies indicate that increasing the targeting activity of EGSs in directing human RNase P to cleave an mRNA in vitro can lead to better efficacies of the EGSs in inducing RNase P-mediated inhibition of the expression of the target mRNA in cultured cells. This chapter will describe the procedure for the generation of highly functional EGSs by in vitro selection. We also describe protocols for in vitro evaluation of the activity of the EGSs. These methods should provide general guidelines for using in vitro selection for generating highly active EGSs for gene-targeting applications.

  12. Monitoring intracellular cavitation during selective targeting of the retinal pigment epithelium

    Science.gov (United States)

    Alt, Clemens; Pitsillides, Costas M.; Roegener, Jan; Lin, Charles P.

    2003-07-01

    PURPOSE Selective targeting of the Retinal Pigment Epithelium (RPE), by either applying trains of microsecond laser pulses or, in our approach, by repetitively scanning a tightly focused spot across the retina, achieves destruction of RPE cells while avoiding damage to the overlying photoreceptors. Both techniques have been demonstrated as attractive methods for the treatment of retinal diseases that are caused by a dysfunction of the RPE. Because the lesions are ophthalmoscopically invisible, an online control system that monitors cell death during irradiation is essential to ensure efficient and selective treatment in a clinical application. MATERIALS AND METHODS Bubble formation inside the RPE cells has been shown to be the cell damage mechanism for nano- and picosecond pulses. We built an optical system to investigate whether the same mechanism extends into the microsecond regime. The system detects changes in backscattered light of the irradiating beam during exposure. Samples of young bovine eyes were exposed in vitro using single pulses ranging from 3 μs to 50 μs. Using the viability assay calcein-AM the ED50 threshold for cell death was determined and compared to the threshold for bubble formation. We also set up a detection system on our slit lamp adapted scanning system in order to determine the feasibility of monitoring threshold RPE damage during selective laser treatment in vivo. RESULTS AND DISCUSSION Intracellular cavitation was detected as a transient increase in backscattering signal, either of an external probe beam or of the irradiation beam itself. Monitoring with the irradiation beam is both simpler and more sensitive. We found the threshold for bubble formation to coincide with the threshold for cell damage for pulse durations up to 20 μs, suggesting that cavitation is the main mechanism of cell damage. For pulse widths longer than 20 μs, the cell damage mechanism appears to be increasingly thermal as the two thresholds diverge. We

  13. Cancer cell-selective promoter recognition accompanies antitumor effect by glucocorticoid receptor-targeted gold nanoparticle

    Science.gov (United States)

    Sau, Samaresh; Agarwalla, Pritha; Mukherjee, Sudip; Bag, Indira; Sreedhar, Bojja; Pal-Bhadra, Manika; Patra, Chitta Ranjan; Banerjee, Rajkumar

    2014-05-01

    Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied on the delivery of `exogenous' genes invoking gene knockdown or replacement. Practically, there are no instances for the nanoparticle-mediated promoter regulation of `endogenous' genes, more so, as a cancer selective phenomenon. In this regard, we report the development of a simple, easily modifiable GNP-formulation, which promoted/up-regulated the expression of a specific category of `endogenous' genes, the glucocorticoid responsive genes. This genetic up-regulation was induced in only cancer cells by modified GNP-mediated transcriptional activation of its cytoplasmic receptor, glucocorticoid receptor (GR). Normal cells and their GR remained primarily unperturbed by this GNP-formulation. The most potent gene up-regulating GNP-formulation down-regulated a cancer-specific proliferative signal, phospho-Akt in cancer cells, which accompanied retardation of tumor growth in the murine melanoma model. We show that GR-targeted GNPs may find potential use in the targeting and modulation of genetic information in cancer towards developing novel anticancer therapeutics.Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied

  14. Label-Free Bottom-Up Proteomic Workflow for Simultaneously Assessing the Target Specificity of Covalent Drug Candidates and Their Off-Target Reactivity to Selected Proteins.

    Science.gov (United States)

    Yang, Yanou; Shu, Yue-Zhong; Humphreys, W Griffith

    2016-01-19

    Although designed covalent inhibitors as drug candidates offer several unique advantages over conventional reversible inhibitors, including high potency and the potential for less frequent dosing, there is a general tendency to avoid the covalent mode of action in drug discovery programs due to concerns regarding immune-mediated toxicity that can arise from indiscriminate reactivity with off-target proteins. Therefore, the ability to assess off-target reactivity relative to target specificity is desirable for optimizing covalent drug candidates in the early discovery stage. One concern with current surrogate nucleophile trapping approaches is that they employ a simplistic model nucleophile such as glutathione, which may not reliably reflect the covalent interactions with cellular or extracellular proteins. One way to get a more relevant reactivity assessment is to directly measure the ability of an inhibitor to covalently modify nucelophilic amino acids on biologically relevant proteins, both on- and off-target. In this article, we describe a label-free bottom-up proteomic workflow for simultaneous evaluation of target binding and off-target reactivity of covalent drug candidates to selected proteins at the peptide level. Ibrutinib, a covalent drug targeting the active site of BTK protein, was used as a model compound to demonstrate the feasibility of the workflow. The compound was incubated with a mixture of target protein, Bruton's tyrosine kinase (BTK), and two abundant proteins in blood, hemoglobin (Hb) and human serum albumin (HSA), and then the ibrutinib modification sites were determined utilizing a bottom-up proteomic approach. A non-BTK specific model compound (1) known to modify cysteine residues was also included. By comparing the extent of off-target modifications to the targeted BTK C481 binding in a wide compound concentration range, we were able to determine the concentration where maximum target binding was achieved with minimal off-target

  15. A Randomized Controlled Trial Targeting Alcohol Use and Sexual Assault Risk among College Women at High Risk for Victimization

    Science.gov (United States)

    Gilmore, Amanda K.; Lewis, Melissa A.; George, William H.

    2015-01-01

    Current sexual assault risk reduction programs do not target alcohol use despite the widespread knowledge that alcohol use is a risk factor for being victimized. The current study assessed the effectiveness of a web-based combined sexual assault risk and alcohol use reduction program using a randomized control trial. A total of 207 college women between the ages of 18 and 20 who engaged in heavy episodic drinking were randomized to one of five conditions: full assessment only control condition, sexual assault risk reduction condition, alcohol use reduction condition, combined sexual assault risk and alcohol use reduction condition, and a minimal assessment only condition. Participants completed a 3-month follow-up survey on alcohol-related sexual assault outcomes, sexual assault outcomes, and alcohol use outcomes. Significant interactions revealed that women with higher incidence and severity of sexual assault at baseline experienced less incapacitated attempted or completed rapes, less incidence/severity of sexual assaults, and engaged in less heavy episodic drinking compared to the control condition at the 3-month follow-up. Web-based risk reduction programs targeting both sexual assault and alcohol use may be the most effective way to target the highest risk sample of college students for sexual assault: those with a sexual assault history and those who engage in heavy episodic drinking. PMID:26408290

  16. A randomized controlled trial targeting alcohol use and sexual assault risk among college women at high risk for victimization.

    Science.gov (United States)

    Gilmore, Amanda K; Lewis, Melissa A; George, William H

    2015-11-01

    Sexual assault risk reduction programs do not target alcohol use despite the widespread knowledge that alcohol use is a risk factor for being victimized. The current study assessed the effectiveness of a web-based combined sexual assault risk and alcohol use reduction program using a randomized control trial. A total of 207 college women between the ages of 18 and 20 who engaged in heavy episodic drinking were randomized to one of five conditions: full assessment only control condition, sexual assault risk reduction condition, alcohol use reduction condition, combined sexual assault risk and alcohol use reduction condition, and a minimal assessment only condition. Participants completed a 3-month follow-up survey on alcohol-related sexual assault outcomes, sexual assault outcomes, and alcohol use outcomes. Significant interactions revealed that women with higher severity of sexual assault at baseline experienced less incapacitated attempted or completed rapes, less severity of sexual assaults, and engaged in less heavy episodic drinking compared to the control condition at the 3-month follow-up. Web-based risk reduction programs targeting both sexual assault and alcohol use may be the most effective way to target the highest risk sample of college students for sexual assault: those with a sexual assault history and those who engage in heavy episodic drinking. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Postsynaptic pyramidal target selection by descending layer III pyramidal axons: dual intracellular recordings and biocytin filling in slices of rat neocortex.

    Science.gov (United States)

    Thomson, A M; Bannister, A P

    1998-06-01

    Paired intracellular recordings in slices of adult rat neocortex with biocytin filling of synaptically connected neurons were used to investigate the pyramidal targets, in layer V, of layer III pyramidal axons. The time-course and sensitivity of excitatory postsynaptic potentials to current injected at the soma, and locations of close appositions between presynaptic axons and postsynaptic dendrites, indicated that the majority of contributory synapses were located in layer V. Within a "column" of tissue, radius < or = 250 microm, the probability that a randomly selected layer III pyramid innervated a layer V pyramid was 1 in 4 if the target cell was a burst firing pyramid with an apical dendritic tuft in layers II/I. If, however, the potential target was a regular spiking pyramid, the probability of connectivity was only 1 in 40, and none of the 13 anatomically identified postsynaptic layer V targets had a slender apical dendrite terminating in layers IV/III. Morphological reconstructions indicated that layer III pyramids select target layer V cells whose apical dendrites pass within 50-100 microm of the soma of the presynaptic pyramid in layer III and which have overlapping apical dendritic tufts in the superficial layers. The probability that a layer V cell would innervate a layer III pyramid lying within 250 microm of its apical dendrite was much lower (one in 58). Both presynaptic layer III pyramids and their large postsynaptic layer V targets could therefore access similar inputs in layers I/II, while small layer V pyramids could not. One prediction from the present data would be that neither descending layer V inputs to the striatum or thalamus, nor transcallosal connections would be readily activated by longer distance cortico-cortical "feedback" connections that terminated in layers I/II. These could, however, activate corticofugal pathways to the superior colliculus or pons, both directly and via layer III.

  18. Differential function of RNCAM isoforms in precise target selection of olfactory sensory neurons.

    Science.gov (United States)

    Alenius, Mattias; Bohm, Staffan

    2003-03-01

    Olfactory sensory neurons (OSNs) are individually specified to express one odorant receptor (OR) gene among approximately 1000 different and project with precision to topographically defined convergence sites, the glomeruli, in the olfactory bulb. Although ORs partially determine the location of convergence sites, the mechanism ensuring that axons with different OR identities do not co-converge is unknown. RNCAM (OCAM, NCAM2) is assumed to regulate a broad zonal segregation of projections by virtue of being a homophilic cell adhesion molecule that is selectively expressed on axons terminating in a defined olfactory bulb region. We have identified NADPH diaphorase activity as being an independent marker for RNCAM-negative axons. Analyses of transgenic mice that ectopically express RNCAM in NADPH diaphorase-positive OSNs show that the postulated function of RNCAM in mediating zone-specific segregation of axons is unlikely. Instead, analyses of one OR-specific OSN subpopulation (P2) reveal that elevated RNCAM levels result in an increased number of P2 axons that incorrectly co-converge with axons of other OR identities. Both Gpi-anchored and transmembrane-bound RNCAM isoforms are localized on axons in the nerve layer, while the transmembrane-bound RNCAM is the predominant isoform on axon terminals within glomeruli. Overexpressing transmembrane-bound RNCAM results in co-convergence events close to the correct target glomeruli. By contrast, overexpression of Gpi-anchored RNCAM results in axons that can bypass the correct target before co-converging on glomeruli located at a distance. The phenotype specific for Gpi-anchored RNCAM is suppressed in mice overexpressing both isoforms, which suggests that two distinct RNCAM isoform-dependent activities influence segregation of OR-defined axon subclasses.

  19. A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network

    Directory of Open Access Journals (Sweden)

    Ji She

    2016-12-01

    Full Text Available Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance.

  20. A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network.

    Science.gov (United States)

    She, Ji; Wang, Fei; Zhou, Jianjiang

    2016-12-21

    Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI) performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI) threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance.

  1. Isolation of novel single-chain Cro proteins targeted for binding to the bcl-2 transcription initiation site by repertoire selection and subunit combinatorics.

    Science.gov (United States)

    Jonas, Kristina; Van Der Vries, Erhard; Nilsson, Mikael T I; Widersten, Mikael

    2005-11-01

    New designed DNA-binding proteins may be recruited to act as transcriptional regulators and could provide new therapeutic agents in the treatment of genetic disorders such as cancer. We have isolated tailored DNA-binding proteins selected for affinity to a region spanning the transcription initiation site of the human bcl-2 gene. The proteins were derived from a single-chain derivative of the lambda Cro protein (scCro), randomly mutated in its recognition helices to construct libraries of protein variants of distinct DNA-binding properties. By phage display-afforded affinity selections combined with recombination of shuffled subunits, protein variants were isolated, which displayed high affinity for the target bcl-2 sequence, as determined by electrophoretic mobility shift and biosensor assays. The proteins analyzed were moderately sequence-specific but provide a starting point for further maturation of desired function.

  2. Control group selection in critical care randomized controlled trials evaluating interventional strategies: An ethical assessment.

    Science.gov (United States)

    Silverman, Henry J; Miller, Franklin G

    2004-03-01

    Ethical concern has been raised with critical care randomized controlled trials in which the standard of care reflects a broad range of clinical practices. Commentators have argued that trials without an unrestricted control group, in which standard practices are implemented at the discretion of the attending physician, lack the ability to redefine the standard of care and might expose subjects to excessive harms due to an inability to stop early. To develop a framework for analyzing control group selection for critical care trials. Ethical analysis. A key ethical variable in trial design is the extent with which the control group adequately reflects standard care practices. Such a control group might incorporate either the "unrestricted" practices of physicians or a protocol that specifies and restricts the parameters of standard practices. Control group selection should be determined with respect to the following ethical objectives of trial design: 1) clinical value, 2) scientific validity, 3) efficiency and feasibility, and 4) protection of human subjects. Because these objectives may conflict, control group selection will involve trade-offs and compromises. Trials using a protocolized rather than an unrestricted standard care control group will likely have enhanced validity. However, if the protocolized control group lacks representativeness to standard care practices, then trials that use such groups will offer less clinical value and could provide less assurance of protecting subjects compared with trials that use unrestricted control groups. For trials evaluating contrasting strategies that do not adequately represent standard practices, use of a third group that is more representative of standard practices will enhance clinical value and increase the ability to stop early if needed to protect subjects. These advantages might come at the expense of efficiency and feasibility. Weighing and balancing the competing ethical objectives of trial design should be

  3. Target selected treatment with levamisole to control the development of anthelmintic resistance in a sheep flock.

    Science.gov (United States)

    Chagas, Ana Carolina de Souza; Domingues, Luciana Ferreira; Gaínza, Yousmel Alemán; Barioni-Júnior, Waldomiro; Esteves, Sérgio Novita; Niciura, Simone Cristina Méo

    2016-03-01

    Levamisole phosphate, chosen based on its 100 % efficacy demonstrated by a previous fecal egg count reduction test (FECRT), was used as the exclusive anthelmintic treatment in the Embrapa Southeast Livestock sheep flock from 2009 to 2014 in a target selected treatment scheme. In the present study, the effectiveness of this nematode control scheme was evaluated after 5 years by FECRT, larval development test (LDT), and a molecular test to assess the development of levamisole resistance in Haemonchus contortus. Animals were submitted to treatments with albendazole, levamisole, closantel, ivermectin, moxidectin, and monepantel. Eggs per gram of feces (EPG) counts and fecal cultures were performed, and anthelmintic efficacy was calculated by the RESO 4.0 program. The helminths of the flock (GIN Embrapa2014) were compared to susceptible (McMaster) and resistant (Embrapa2010) H. contortus isolates in the LDT to estimate the LC50 and LC90 of levamisole and in a molecular test to evaluate the 63-bp indel in the acr8 gene associated with levamisole resistance. In the FECRT, parasites were susceptible to monepantel (99.6 %) and closantel (98.3 %), but resistant to moxidectin (93.8 %), levamisole (70.4 %), ivermectin (48.1 %), and albendazole (0 %). In the coproculture on D14, and the control group presented 80 % H. contortus and 20 % Trichostrongylus sp., while in the monepantel group L1 were observed as well as Oesophagostomum sp. L3. LDT and resistance factors provided good separation between susceptible and resistant parasites. The genotypic frequencies of the 63-bp insertion in the acr8 gene in H. contortus were 11.9, 6.7, and 0 % in GIN Embrapa2014, Embrapa2010, and McMaster isolates, respectively. After 5 years of exclusive use, the nematodes developed resistance to levamisole, detected by FECRT and by increase in LC50 and LC90 for levamisole in the LDT. The 63-bp indel was not confirmed as a molecular marker of levamisole resistance in our isolates. The target

  4. Selective Inhibition of STAT3 Phosphorylation Using a Nuclear-Targeted Kinase Inhibitor.

    Science.gov (United States)

    Bartolowits, Matthew D; Brown, Wells; Ali, Remah; Pedley, Anthony M; Chen, Qingshou; Harvey, Kyle E; Wendt, Michael K; Davisson, Vincent Jo

    2017-09-15

    The discovery of compounds that selectively modulate signaling and effector proteins downstream of EGFR could have important implications for understanding specific roles for pathway activation. A complicating factor for receptor tyrosine kinases is their capacity to be translocated to the nucleus upon ligand engagement. Once localized in subcellular compartments like the nucleus, the roles for EGFR take on additional features, many of which are still being revealed. Additionally, nuclear localization of EGFR has been implicated in downstream events that have significance for therapy resistance and disease progression. The challenges to addressing the differential roles for EGFR in the nucleus motivated experimental approaches that can selectively modulate its subcellular function. By adding modifications to the established EGFR kinase inhibitor gefitinib, an approach to small molecule conjugates with a unique nuclear-targeting peptoid sequence was tested in both human and murine breast tumor cell models for their capacity to inhibit EGF-stimulated activation of ERK1/2 and STAT3. While gefitinib alone inhibits both of these downstream effectors, data acquired here indicate that compartmentalization of the gefitinib conjugates allows for pathway specific inhibition of STAT3 while not affecting ERK1/2 signaling. The inhibitor conjugates offered a more direct route to evaluate the role of EGF-stimulated epithelial-to-mesenchymal transition in these breast cancer cell models. These conjugates revealed that STAT3 activation is not involved in EGF-induced EMT, and instead utilization of the cytoplasmic MAP kinase signaling pathway is critical to this process. This is the first example of a conjugate kinase inhibitor capable of partitioning to the nucleus and offers a new approach to enhancing kinase inhibitor specificity.

  5. Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

    Science.gov (United States)

    Eide, Christopher A.; Kaempf, Andy; Khanna, Vishesh; Savage, Samantha L.; Rofelty, Angela; English, Isabel; Ho, Hibery; Pandya, Ravi; Bolosky, William J.; Poon, Hoifung; Deininger, Michael W.; Collins, Robert; Swords, Ronan T.; Watts, Justin; Pollyea, Daniel A.; Medeiros, Bruno C.; Traer, Elie; Tognon, Cristina E.; Mori, Motomi; Druker, Brian J.; Tyner, Jeffrey W.

    2017-01-01

    Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies. PMID:28784769

  6. Novel Method of Unambiguous Moving Target Detection in Pulse-Doppler Radar with Random Pulse Repetition Interval

    Directory of Open Access Journals (Sweden)

    Liu Zhen

    2012-03-01

    Full Text Available Blind zones and ambiguities in range and velocity measurement are two important issues in traditional pulse-Doppler radar. By generating random deviations with respect to a mean Pulse Repetition Interval (PRI, this paper proposes a novel algorithm of Moving Target Detection (MTD based on the Compressed Sensing (CS theory, in which the random deviations of the PRIare converted to the Restricted Isometry Property (RIP of the observing matrix. The ambiguities of range and velocity are eliminated by designing the signal parameters. The simulation results demonstrate that this scheme has high performance of detection, and there is no ambiguity and blind zones as well. It can also shorten the coherent processing interval compared to traditional staggered PRI mode because only one pulse train is needed instead of several trains.

  7. Interval MULTIMOORA method with target values of attributes based on interval distance and preference degree: biomaterials selection

    Science.gov (United States)

    Hafezalkotob, Arian; Hafezalkotob, Ashkan

    2017-12-01

    A target-based MADM method covers beneficial and non-beneficial attributes besides target values for some attributes. Such techniques are considered as the comprehensive forms of MADM approaches. Target-based MADM methods can also be used in traditional decision-making problems in which beneficial and non-beneficial attributes only exist. In many practical selection problems, some attributes have given target values. The values of decision matrix and target-based attributes can be provided as intervals in some of such problems. Some target-based decision-making methods have recently been developed; however, a research gap exists in the area of MADM techniques with target-based attributes under uncertainty of information. We extend the MULTIMOORA method for solving practical material selection problems in which material properties and their target values are given as interval numbers. We employ various concepts of interval computations to reduce degeneration of uncertain data. In this regard, we use interval arithmetic and introduce innovative formula for interval distance of interval numbers to create interval target-based normalization technique. Furthermore, we use a pairwise preference matrix based on the concept of degree of preference of interval numbers to calculate the maximum, minimum, and ranking of these numbers. Two decision-making problems regarding biomaterials selection of hip and knee prostheses are discussed. Preference degree-based ranking lists for subordinate parts of the extended MULTIMOORA method are generated by calculating the relative degrees of preference for the arranged assessment values of the biomaterials. The resultant rankings for the problem are compared with the outcomes of other target-based models in the literature.

  8. A Randomized Effectiveness Trial of a Behavioral Teacher Program Targeting ADHD Symptoms

    NARCIS (Netherlands)

    Veenman, B.Y.; Luman, M.; Oosterlaan, J.

    2016-01-01

    Objective: This study investigated the effectiveness of the Positivity & Rules Program (PR program), a behavioral teacher program targeting ADHD symptoms in the classroom involving both student-focused and classroom-focused programs. Method: Primary school children with ADHD symptoms (N = 114) were

  9. An Assessment of the Effect of Rotenone on Selected Non-Target Aquatic Fauna

    Science.gov (United States)

    Dalu, Tatenda; Wasserman, Ryan J.; Jordaan, Martine; Froneman, William P.; Weyl, Olaf L. F.

    2015-01-01

    Rotenone, a naturally occurring ketone, is widely employed for the management of invasive fish species. The use of rotenone poses serious challenges to conservation practitioners due to its impacts on non-target organisms including amphibians and macroinvertebrates. Using laboratory studies, we investigated the effects of different rotenone concentrations (0, 12.5, 25, 37.5, 50, 100 μg L-1) on selected invertebrate groups; Aeshnidae, Belostomatids, Decapods, Ephemeroptera, Pulmonata and zooplankton over a period of 18 hours. Based on field observations and body size, we hypothesized that Ephemeropterans and zooplankton would be more susceptible to rotenone than Decapods, Belostomatids and snails. Experimental results supported this hypothesis and mortality and behaviour effects varied considerably between taxa, ranging from no effect (crab Potamonuates sidneyi) to 100% mortality (Daphnia pulex and Paradiaptomus lamellatus). Planktonic invertebrates were particularly sensitive to rotenone even at very low concentrations. Future research should investigate the recovery time of invertebrate communities after the application of rotenone and conduct field assessments assessing the longer term effects of rotenone exposure on the population dynamics of those less sensitive organisms. PMID:26540301

  10. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

    Science.gov (United States)

    Campaner, Elena; Rustighi, Alessandra; Zannini, Alessandro; Cristiani, Alberto; Piazza, Silvano; Ciani, Yari; Kalid, Ori; Golan, Gali; Baloglu, Erkan; Shacham, Sharon; Valsasina, Barbara; Cucchi, Ulisse; Pippione, Agnese Chiara; Lolli, Marco Lucio; Giabbai, Barbara; Storici, Paola; Carloni, Paolo; Rossetti, Giulia; Benvenuti, Federica; Bello, Ezia; D'Incalci, Maurizio; Cappuzzello, Elisa; Rosato, Antonio; Del Sal, Giannino

    2017-06-01

    The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

  11. Tumour‐selective targeting of drug metabolizing enzymes to treat metastatic cancer

    Science.gov (United States)

    Wierdl, Monika; Tsurkan, Lyudmila; Hatfield, M Jason

    2016-01-01

    Carboxylesterases (CEs) are ubiquitous enzymes responsible for the detoxification of ester‐containing xenobiotics. This hydrolysis reaction results in the formation of the corresponding carboxylic acid and alcohol. Due to their highly plastic active site, CEs can hydrolyze structurally very distinct and complex molecules. Because ester groups significantly increase the water solubility of compounds, they are frequently used in the pharmaceutical industry to make relatively insoluble compounds more bioavailable. By default, this results in CEs playing a major role in the distribution and metabolism of these esterified drugs. However, this can be exploited to selectively improve compound hydrolysis, and using specific in vivo targeting techniques can be employed to generate enhanced drug activity. Here, we seek to detail the human CEs involved in esterified molecule hydrolysis, compare and contrast these with CEs present in small mammals and describe novel methods to improve drug therapy by specific delivery of CEs to cells in vivo. Finally, we will discuss the development of such approaches for their potential application towards malignant disease. PMID:27423046

  12. Folic acid-conjugated europium complexes as luminescent probes for selective targeting of cancer cells.

    Science.gov (United States)

    Quici, Silvio; Casoni, Alessandro; Foschi, Francesca; Armelao, Lidia; Bottaro, Gregorio; Seraglia, Roberta; Bolzati, Cristina; Salvarese, Nicola; Carpanese, Debora; Rosato, Antonio

    2015-02-26

    We report the synthesis of three optical probes (Eu(3+)⊂1, Eu(3+)⊂2, and Eu(3+)⊂3) having a luminescent Eu complex (signaling unit) bonded in different positions to folic acid (FA), the folate receptor (FR) targeting unit. The structures of the two regioisomers Eu(3+)⊂1 and Eu(3+)⊂2 were assigned by mass spectrometric experiments. The optical properties and stability of these probes were assessed in phosphate-buffered saline, cell culture medium, rat serum, and cellular lysate, and results indicated that they are chemically and photophysically stable. Cytotoxicity was studied with ovarian cancer cells having high (SKOV-3), intermediate (OVCAR-3), low (IGROV-1), or null (A2780) expression of FRs. The internalized probe, evaluated in SKOV-3, IGROV-1, and A2780 cells, was in the order Eu(3+)⊂2 > Eu(3+)⊂1 > Eu(3+)⊂3. No internalization was observed for A2780 cells. Such results, together with those obtained in competition experiments of FA versus Eu(3+)⊂2 and FA or Eu(3+)⊂2 versus (3)H-FA, indicate that internalization is receptor-mediated and that Eu(3+)⊂2 shows high selectivity and specificity for FR.

  13. The adverse effect of selective cyclooxygenase-2 inhibitor on random skin flap survival in rats.

    Directory of Open Access Journals (Sweden)

    Haiyong Ren

    Full Text Available BACKGROUND: Cyclooxygenase-2(COX-2 inhibitors provide desired analgesic effects after injury or surgery, but evidences suggested they also attenuate wound healing. The study is to investigate the effect of COX-2 inhibitor on random skin flap survival. METHODS: The McFarlane flap model was established in 40 rats and evaluated within two groups, each group gave the same volume of Parecoxib and saline injection for 7 days. The necrotic area of the flap was measured, the specimens of the flap were stained with haematoxylin-eosin(HE for histologic analysis. Immunohistochemical staining was performed to analyse the level of VEGF and COX-2 . RESULTS: 7 days after operation, the flap necrotic area ratio in study group (66.65 ± 2.81% was significantly enlarged than that of the control group(48.81 ± 2.33%(P <0.01. Histological analysis demonstrated angiogenesis with mean vessel density per mm(2 being lower in study group (15.4 ± 4.4 than in control group (27.2 ± 4.1 (P <0.05. To evaluate the expression of COX-2 and VEGF protein in the intermediate area II in the two groups by immunohistochemistry test .The expression of COX-2 in study group was (1022.45 ± 153.1, and in control group was (2638.05 ± 132.2 (P <0.01. The expression of VEGF in the study and control groups were (2779.45 ± 472.0 vs (4938.05 ± 123.6(P <0.01.In the COX-2 inhibitor group, the expressions of COX-2 and VEGF protein were remarkably down-regulated as compared with the control group. CONCLUSION: Selective COX-2 inhibitor had adverse effect on random skin flap survival. Suppression of neovascularization induced by low level of VEGF was supposed to be the biological mechanism.

  14. Capturing the Flatness of a peer-to-peer lending network through random and selected perturbations

    Science.gov (United States)

    Karampourniotis, Panagiotis D.; Singh, Pramesh; Uparna, Jayaram; Horvat, Emoke-Agnes; Szymanski, Boleslaw K.; Korniss, Gyorgy; Bakdash, Jonathan Z.; Uzzi, Brian

    Null models are established tools that have been used in network analysis to uncover various structural patterns. They quantify the deviance of an observed network measure to that given by the null model. We construct a null model for weighted, directed networks to identify biased links (carrying significantly different weights than expected according to the null model) and thus quantify the flatness of the system. Using this model, we study the flatness of Kiva, a large international crownfinancing network of borrowers and lenders, aggregated to the country level. The dataset spans the years from 2006 to 2013. Our longitudinal analysis shows that flatness of the system is reducing over time, meaning the proportion of biased inter-country links is growing. We extend our analysis by testing the robustness of the flatness of the network in perturbations on the links' weights or the nodes themselves. Examples of such perturbations are event shocks (e.g. erecting walls) or regulatory shocks (e.g. Brexit). We find that flatness is unaffected by random shocks, but changes after shocks target links with a large weight or bias. The methods we use to capture the flatness are based on analytics, simulations, and numerical computations using Shannon's maximum entropy. Supported by ARL NS-CTA.

  15. ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines

    Energy Technology Data Exchange (ETDEWEB)

    Zask, Arie; Verheijen, Jeroen C.; Curran, Kevin; Kaplan, Joshua; Richard, David J.; Nowak, Pawel; Malwitz, David J.; Brooijmans, Natasja; Bard, Joel; Svenson, Kristine; Lucas, Judy; Toral-Barza, Lourdes; Zhang, Wei-Guo; Hollander, Irwin; Gibbons, James J.; Abraham, Robert T.; Ayral-Kaloustian, Semiramis; Mansour, Tarek S.; Yu, Ker; (Wyeth)

    2009-09-18

    The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

  16. Selection of binding targets in parasites using phage-display and aptamer libraries in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Renata Rosito Tonelli

    2013-01-01

    Full Text Available Parasite infections are largely dependent on interactions between pathogen and different host cell populations to guarantee a successful infectious process. This is particularly true for obligatory intracellular parasites as Plasmodium, Toxoplasma, Leishmania, to name a few. Adhesion to and entry into the cell are essential steps requiring specific parasite and host cell molecules. The large amount of possible involved molecules poses additional difficulties for their identification by the classical biochemical approaches. In this respect, the search for alternative techniques should be pursued. Among them two powerful methodologies can be employed, both relying upon the construction of highly diverse combinatorial libraries of peptides or oligonucleotides that randomly bind with high affinity to targets on the cell surface and are selectively displaced by putative ligands. These are, respectively, the peptide-based phage display and the oligonucleotide-based aptamer techniques.The phage display technique has been extensively employed for the identification of novel ligands in vitro and in vivo in different areas such as cancer, vaccine development and epitope mapping. Particularly, phage display has been employed in the investigation of pathogen-host interactions. Although this methodology has been used for some parasites with encouraging results, in trypanosomatids its use is, as yet, scanty. RNA and DNA aptamers, developed by the SELEX process (Systematic Evolution of Ligands by Exponential Enrichment, were described over two decades ago and since then contributed to a large number of structured nucleic acids for diagnostic or therapeutic purposes or for the understanding of the cell biology. Similarly to the phage display technique scarce use of the SELEX process has been used in the probing of parasite-host interaction.In this review, an overall survey on the use of both phage display and aptamer technologies in different pathogenic

  17. Target Selection Recommendations Based on Impact of Deep Brain Stimulation Surgeries on Nonmotor Symptoms of Parkinson′s Disease

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Wang

    2015-01-01

    Full Text Available Objective: This review examines the evidence that deep brain stimulation (DBS has extensive impact on nonmotor symptoms (NMSs of patients with Parkinson′s disease (PD. Data Sources: We retrieved information from the PubMed database up to September, 2015, using various search terms and their combinations including PD, NMSs, DBS, globus pallidus internus (GPi, subthalamic nucleus (STN, and ventral intermediate thalamic nucleus. Study Selection: We included data from peer-reviewed journals on impacts of DBS on neuropsychological profiles, sensory function, autonomic symptoms, weight changes, and sleep disturbances. For psychological symptoms and cognitive impairment, we tried to use more reliable proofs: Random, control, multicenter, large sample sizes, and long period follow-up clinical studies. We categorized the NMSs into four groups: those that would improve definitively following DBS; those that are not significantly affected by DBS; those that remain controversial on their surgical benefit; and those that can be worsened by DBS. Results: In general, it seems to be an overall beneficial effect of DBS on NMSs, such as sensory, sleep, gastrointestinal, sweating, cardiovascular, odor, urological symptoms, and sexual dysfunction, GPi-DBS may produce similar results; Both STN and Gpi-DBS are safe with regard to cognition and psychology over long-term follow-up, though verbal fluency decline is related to DBS; The impact of DBS on behavioral addictions and dysphagia is still uncertain. Conclusions: As the motor effects of STN-DBS and GPi-DBS are similar, NMSs may determine the target choice in surgery of future patients.

  18. Fundamental movement skills in preschoolers: a randomized controlled trial targeting object control proficiency.

    Science.gov (United States)

    Donath, L; Faude, O; Hagmann, S; Roth, R; Zahner, L

    2015-11-01

    Adequately developed fundamental movement skills, particularly object control dimensions, are considered essential to learn more complex movement patterns and to increase the likelihood to successfully participate in organized and non-organized sports during later years. Thus, the present randomized controlled trial aimed at improving object control dimensions at an early state in a kindergarten setting. Catching, throwing, kicking, rolling and stationary dribbling were assessed via gross motor development 2 (TGMD-2) testing in 41 normally developed preschoolers. On a cluster-randomized basis [strata: age, sex and body mass index (BMI)], three kindergartens were randomly assigned to an intervention group (n = 22, INT, age: 4.6 ± 1.0 years; BMI: 16.2 ± 1.1 kg/m(2) ) and three to a control group (n = 19, CON: age: 4.5 ± 1.2 years; BMI: 16.8 ± 1.2 kg/m(2) ). Twelve structured training sessions were given within 6 weeks (12 sessions). The total training volume was 330 min. Moderate time × group interaction were observed for the total sum score (Δ+22%, P = 0.05) and dribbling (Δ+41%, P = 0.002). Adjusting for baseline differences analyses of covariance did not affect these results. Interestingly, likely to most likely practically worthwhile effects were detected for the total sum score, catching and dribbling. Object control dimensions such as dribbling and catching that apparently rely on rhythmical movement patterns and anticipatory eye-hand coordination seem to benefit from short-term object control training. These skills are considered important for successful team-sport participation and appropriate sportive motor development. © 2015 John Wiley & Sons Ltd.

  19. Cell-Mediated Cytotoxicity Toward Measles Virus-Infected Target Cells in Randomly Bred Syrian Hamsters

    OpenAIRE

    Cremer, Natalie E.; O'Keefe, Beatrice; Hagens, Shirley J.; Diggs, Janice

    1982-01-01

    Cell-mediated cytotoxicity (CMC) toward measles virus-infected cells was studied by a 51Cr release assay with spleen cells from hamsters inoculated with measles virus (strain Lec) or control antigen and with spleen cells from normal hamsters. Spleen cells from measles virus-inoculated hamsters showed greater CMC toward infected than toward noninfected target cells (designated specific CMC). Specific CMC was maximal 7 days after virus inoculation and was declining by 9 to 10 days. Effector cel...

  20. New Strategies for the Next Generation of Matrix-Metalloproteinase Inhibitors: Selectively Targeting Membrane-Anchored MMPs with Therapeutic Antibodies

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2011-01-01

    Full Text Available MMP intervention strategies have met with limited clinical success due to severe toxicities. In particular, treatment with broad-spectrum MMP-inhibitors (MMPIs caused musculoskeletal pain and inflammation. Selectivity may be essential for realizing the clinical potential of MMPIs. Here we review discoveries pinpointing membrane-bound MMPs as mediators of mechanisms underlying cancer and inflammation and as possible therapeutic targets for prevention/treatment of these diseases. We discuss strategies to target these therapeutic proteases using highly selective inhibitory agents (i.e., human blocking antibodies against individual membrane-bound MMPs.

  1. Attention Blinks for Selection, Not Perception or Memory: Reading Sentences and Reporting Targets

    Science.gov (United States)

    Potter, Mary C.; Wyble, Brad; Olejarczyk, Jennifer

    2011-01-01

    In whole report, a sentence presented sequentially at the rate of about 10 words/s can be recalled accurately, whereas if the task is to report only two target words (e.g., red words), the second target suffers an attentional blink if it appears shortly after the first target. If these two tasks are carried out simultaneously, is there an…

  2. Random genetic drift, natural selection, and noise in human cranial evolution.

    Science.gov (United States)

    Roseman, Charles C

    2016-08-01

    This study assesses the extent to which relationships among groups complicate comparative studies of adaptation in recent human cranial variation and the extent to which departures from neutral additive models of evolution hinder the reconstruction of population relationships among groups using cranial morphology. Using a maximum likelihood evolutionary model fitting approach and a mixed population genomic and cranial data set, I evaluate the relative fits of several widely used models of human cranial evolution. Moreover, I compare the goodness of fit of models of cranial evolution constrained by genomic variation to test hypotheses about population specific departures from neutrality. Models from population genomics are much better fits to cranial variation than are traditional models from comparative human biology. There is not enough evolutionary information in the cranium to reconstruct much of recent human evolution but the influence of population history on cranial variation is strong enough to cause comparative studies of adaptation serious difficulties. Deviations from a model of random genetic drift along a tree-like population history show the importance of environmental effects, gene flow, and/or natural selection on human cranial variation. Moreover, there is a strong signal of the effect of natural selection or an environmental factor on a group of humans from Siberia. The evolution of the human cranium is complex and no one evolutionary process has prevailed at the expense of all others. A holistic unification of phenome, genome, and environmental context, gives us a strong point of purchase on these problems, which is unavailable to any one traditional approach alone. Am J Phys Anthropol 160:582-592, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Chemical biology based on target-selective degradation of proteins and carbohydrates using light-activatable organic molecules.

    Science.gov (United States)

    Toshima, Kazunobu

    2013-05-01

    Proteins and carbohydrates play crucial roles in a wide range of biological processes, including serious diseases. The development of novel and innovative methods for selective control of specific proteins and carbohydrates functions has attracted much attention in the field of chemical biology. In this account article, the development of novel chemical tools, which can degrade target proteins and carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced. This novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of proteins and carbohydrates but also novel therapeutic drugs targeting proteins and carbohydrates.

  4. Guided imagery targeting exercise, food cravings, and stress: a multi-modal randomized feasibility trial.

    Science.gov (United States)

    Giacobbi, Peter; Long, Dustin; Nolan, Richard; Shawley, Samantha; Johnson, Kelsey; Misra, Ranjita

    2017-08-01

    The purpose of this randomized wait-list controlled trial was to test the feasibility and preliminary efficacy of a guided imagery based multi-behavior intervention intended to address psychological stress, food cravings, and physical activity. Personalized guided imagery scripts were created and participants were instructed to practice guided imagery every day for 35 consecutive days. Of 48 women who enrolled, we report comparisons between 16 randomized to treatment with 19 who were wait-listed (overall Mage = 45.50; Mbodymassindex = 31.43). Study completers reported 89% compliance with practicing guided imagery during the intervention. A significant time-by-group interaction was observed with reductions in food cravings and increases in physical activity compared with wait-list controls. Telephone-based multi-behavior interventions that utilize guided imagery to address food cravings and exercise behavior appear to be acceptable for overweight and obese women. Future phone-based guided imagery research testing this skill to address multiple health behaviors is justified.

  5. CURE-SMOTE algorithm and hybrid algorithm for feature selection and parameter optimization based on random forests.

    Science.gov (United States)

    Ma, Li; Fan, Suohai

    2017-03-14

    The random forests algorithm is a type of classifier with prominent universality, a wide application range, and robustness for avoiding overfitting. But there are still some drawbacks to random forests. Therefore, to improve the performance of random forests, this paper seeks to improve imbalanced data processing, feature selection and parameter optimization. We propose the CURE-SMOTE algorithm for the imbalanced data classification problem. Experiments on imbalanced UCI data reveal that the combination of Clustering Using Representatives (CURE) enhances the original synthetic minority oversampling technique (SMOTE) algorithms effectively compared with the classification results on the original data using random sampling, Borderline-SMOTE1, safe-level SMOTE, C-SMOTE, and k-means-SMOTE. Additionally, the hybrid RF (random forests) algorithm has been proposed for feature selection and parameter optimization, which uses the minimum out of bag (OOB) data error as its objective function. Simulation results on binary and higher-dimensional data indicate that the proposed hybrid RF algorithms, hybrid genetic-random forests algorithm, hybrid particle swarm-random forests algorithm and hybrid fish swarm-random forests algorithm can achieve the minimum OOB error and show the best generalization ability. The training set produced from the proposed CURE-SMOTE algorithm is closer to the original data distribution because it contains minimal noise. Thus, better classification results are produced from this feasible and effective algorithm. Moreover, the hybrid algorithm's F-value, G-mean, AUC and OOB scores demonstrate that they surpass the performance of the original RF algorithm. Hence, this hybrid algorithm provides a new way to perform feature selection and parameter optimization.

  6. Noise-induced hearing loss in randomly selected New York dairy farmers.

    Science.gov (United States)

    May, J J; Marvel, M; Regan, M; Marvel, L H; Pratt, D S

    1990-01-01

    To understand better the effects of noise levels associated with dairy farming, we randomly selected 49 full-time dairy farmers from an established cohort. Medical and occupational histories were taken and standard audiometric testing was done. Forty-six males (94%) and three females (6%) with a mean age of 43.5 (+/- 13) years and an average of 29.4 (+/- 14) years in farming were tested. Pure Tone Average thresholds (PTA4) at 0.5, 1.0, 2.0, and 3.0 kHz plus High Frequency Average thresholds (HFA3) at 3.0, 4.0, and 6.0 kHz were calculated. Subjects with a loss of greater than or equal to 20 db in either ear were considered abnormal. Eighteen subjects (37%) had abnormal PTA4S and 32 (65%) abnormal HFA3S. The left ear was more severely affected in both groups (p less than or equal to .05, t-test). Significant associations were found between hearing loss and years worked (odds ratio 4.1, r = .53) and age (odds ratio 4.1, r = .59). No association could be found between hearing loss and measles; mumps; previous ear infections; or use of power tools, guns, motorcycles, snowmobiles, or stereo headphones. Our data suggest that among farmers, substantial hearing loss occurs especially in the high-frequency ranges. Presbycusis is an important confounding variable.

  7. Modeling Slotted Aloha as a Stochastic Game with Random Discrete Power Selection Algorithms

    Directory of Open Access Journals (Sweden)

    Rachid El-Azouzi

    2009-01-01

    Full Text Available We consider the uplink case of a cellular system where bufferless mobiles transmit over a common channel to a base station, using the slotted aloha medium access protocol. We study the performance of this system under several power differentiation schemes. Indeed, we consider a random set of selectable transmission powers and further study the impact of priorities given either to new arrival packets or to the backlogged ones. Later, we address a general capture model where a mobile transmits successfully a packet if its instantaneous SINR (signal to interferences plus noise ratio is lager than some fixed threshold. Under this capture model, we analyze both the cooperative team in which a common goal is jointly optimized as well as the noncooperative game problem where mobiles reach to optimize their own objectives. Furthermore, we derive the throughput and the expected delay and use them as the objectives to optimize and provide a stability analysis as alternative study. Exhaustive performance evaluations were carried out, we show that schemes with power differentiation improve significantly the individual as well as global performances, and could eliminate in some cases the bi-stable nature of slotted aloha.

  8. Dropouts and Compliance in Exercise Interventions Targeting Bone Mineral Density in Adults: A Meta-Analysis of Randomized Controlled Trials

    Directory of Open Access Journals (Sweden)

    George A. Kelley

    2013-01-01

    Full Text Available Background. Dropouts and compliance to exercise interventions targeting bone mineral density (BMD in adults are not well established. The purpose of this study was to address that gap. Methods. Meta-analysis of randomized controlled exercise intervention trials in adults ≥18 years of age. The primary outcomes were dropouts in the exercise and control groups as well as compliance to the exercise interventions. A random-effects model was used to pool results. Moderator analyses were conducted using mixed-effects ANOVA-like models and metaregression. Statistical significance was set at . Results. Thirty-six studies representing 3,297 participants (1,855 exercise, 1,442 control were included. Dropout rates in the exercise and control groups averaged 20.9% (95% CI 16.7%–25.9% and 15.9% (11.8%–21.1% while compliance to exercise was 76.3% (71.7%–80.3%. For both exercise and control groups, greater dropout rates were associated with studies conducted in the USA versus other countries, females versus males, premenopausal versus postmenopausal women, younger versus older participants, longer studies (controls only, and high- versus moderate-intensity training (exercisers only. Greater compliance to exercise was associated with being female, home- or facility-based exercise versus both, and shorter studies. Conclusion. These findings provide important information for researchers and practitioners with respect to exercise programs targeting BMD in adults.

  9. A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins.

    Science.gov (United States)

    Peigneur, Steve; Béress, László; Möller, Carolina; Marí, Frank; Forssmann, Wolf-Georg; Tytgat, Jan

    2012-12-01

    APETx3, a novel peptide isolated from the sea anemone Anthopleura elegantissima, is a naturally occurring mutant from APETx1, only differing by a Thr to Pro substitution at position 3. APETx1 is believed to be a selective modulator of human ether-á-go-go related gene (hERG) potassium channels with a K(d) of 34 nM. In this study, APETx1, 2, and 3 have been subjected to an electrophysiological screening on a wide range of 24 ion channels expressed in Xenopus laevis oocytes: 10 cloned voltage-gated sodium channels (Na(V) 1.2-Na(V)1.8, the insect channels DmNa(V)1, BgNa(V)1-1a, and the arachnid channel VdNa(V)1) and 14 cloned voltage-gated potassium channels (K(V)1.1-K(V)1.6, K(V)2.1, K(V)3.1, K(V)4.2, K(V)4.3, K(V)7.2, K(V)7.4, hERG, and the insect channel Shaker IR). Surprisingly, the Thr3Pro substitution results in a complete abolishment of APETx3 modulation on hERG channels and provides this toxin the ability to become a potent (EC(50) 276 nM) modulator of voltage-gated sodium channels (Na(V)s) because it slows down the inactivation of mammalian and insect Na(V) channels. Our study also shows that the homologous toxins APETx1 and APETx2 display promiscuous properties since they are also capable of recognizing Na(V) channels with IC(50) values of 31 nM and 114 nM, respectively, causing an inhibition of the sodium conductance without affecting the inactivation. Our results provide new insights in key residues that allow these sea anemone toxins to recognize distinct ion channels with similar potency but with different modulatory effects. Furthermore, we describe for the first time the target promiscuity of a family of sea anemone toxins thus far believed to be highly selective.

  10. The prediction of organelle-targeting peptides in eukaryotic proteins with Grammatical-Restrained Hidden Conditional Random Fields.

    Science.gov (United States)

    Indio, Valentina; Martelli, Pier Luigi; Savojardo, Castrense; Fariselli, Piero; Casadio, Rita

    2013-04-15

    Targeting peptides are the most important signal controlling the import of nuclear encoded proteins into mitochondria and plastids. In the lack of experimental information, their prediction is an essential step when proteomes are annotated for inferring both the localization and the sequence of mature proteins. We developed TPpred a new predictor of organelle-targeting peptides based on Grammatical-Restrained Hidden Conditional Random Fields. TPpred is trained on a non-redundant dataset of proteins where the presence of a target peptide was experimentally validated, comprising 297 sequences. When tested on the 297 positive and some other 8010 negative examples, TPpred outperformed available methods in both accuracy and Matthews correlation index (96% and 0.58, respectively). Given its very low-false-positive rate (3.0%), TPpred is, therefore, well suited for large-scale analyses at the proteome level. We predicted that from ∼4 to 9% of the sequences of human, Arabidopsis thaliana and yeast proteomes contain targeting peptides and are, therefore, likely to be localized in mitochondria and plastids. TPpred predictions correlate to a good extent with the experimental annotation of the subcellular localization, when available. TPpred was also trained and tested to predict the cleavage site of the organelle-targeting peptide: on this task, the average error of TPpred on mitochondrial and plastidic proteins is 7 and 15 residues, respectively. This value is lower than the error reported by other methods currently available. The TPpred datasets are available at http://biocomp.unibo.it/valentina/TPpred/. TPpred is available on request from the authors. Supplementary data are available at Bioinformatics online.

  11. The prevalence of symptoms associated with pulmonary tuberculosis in randomly selected children from a high burden community

    OpenAIRE

    Marais, B.; Obihara, C; Gie, R.; Schaaf, H; Hesseling, A.; Lombard, C.; Enarson, D; Bateman, E; Beyers, N

    2005-01-01

    Background: Diagnosis of childhood tuberculosis is problematic and symptom based diagnostic approaches are often promoted in high burden settings. This study aimed (i) to document the prevalence of symptoms associated with tuberculosis among randomly selected children living in a high burden community, and (ii) to compare the prevalence of these symptoms in children without tuberculosis to those in children with newly diagnosed tuberculosis.

  12. Identification and Characterization of Genes Involved in Leishmania Pathogenesis: The Potential for Drug Target Selection

    Directory of Open Access Journals (Sweden)

    Robert Duncan

    2011-01-01

    Full Text Available Identifying and characterizing Leishmania donovani genes and the proteins they encode for their role in pathogenesis can reveal the value of this approach for finding new drug targets. Effective drug targets are likely to be proteins differentially expressed or required in the amastigote life cycle stage found in the patient. Several examples and their potential for chemotherapeutic disruption are presented. A pathway nearly ubiquitous in living cells targeted by anticancer drugs, the ubiquitin system, is examined. New findings in ubiquitin and ubiquitin-like modifiers in Leishmania show how disruption of those pathways could point to additional drug targets. The programmed cell death pathway, now recognized among protozoan parasites, is reviewed for some of its components and evidence that suggests they could be targeted for antiparasitic drug therapy. Finally, the endoplasmic reticulum quality control system is involved in secretion of many virulence factors. How disruptions in this pathway reduce virulence as evidence for potential drug targets is presented.

  13. Surveillance for cancer recurrence in long-term young breast cancer survivors randomly selected from a statewide cancer registry.

    Science.gov (United States)

    Jones, Tarsha; Duquette, Debra; Underhill, Meghan; Ming, Chang; Mendelsohn-Victor, Kari E; Anderson, Beth; Milliron, Kara J; Copeland, Glenn; Janz, Nancy K; Northouse, Laurel L; Duffy, Sonia M; Merajver, Sofia D; Katapodi, Maria C

    2018-01-20

    This study examined clinical breast exam (CBE) and mammography surveillance in long-term young breast cancer survivors (YBCS) and identified barriers and facilitators to cancer surveillance practices. Data collected with a self-administered survey from a statewide, randomly selected sample of YBCS diagnosed with invasive breast cancer or ductal carcinoma in situ younger than 45 years old, stratified by race (Black vs. White/Other). Multivariate logistic regression models identified predictors of annual CBEs and mammograms. Among 859 YBCS (n = 340 Black; n = 519 White/Other; mean age = 51.0 ± 5.9; diagnosed 11.0 ± 4.0 years ago), the majority (> 85%) reported an annual CBE and a mammogram. Black YBCS in the study were more likely to report lower rates of annual mammography and more barriers accessing care compared to White/Other YBCS. Having a routine source of care, confidence to use healthcare services, perceived expectations from family members and healthcare providers to engage in cancer surveillance, and motivation to comply with these expectations were significant predictors of having annual CBEs and annual mammograms. Cost-related lack of access to care was a significant barrier to annual mammograms. Routine source of post-treatment care facilitated breast cancer surveillance above national average rates. Persistent disparities regarding access to mammography surveillance were identified for Black YBCS, primarily due to lack of access to routine source of care and high out-of-pocket costs. Public health action targeting cancer surveillance in YBCS should ensure routine source of post-treatment care and address cost-related barriers. Clinical Trials Registration Number: NCT01612338.

  14. Differential privacy-based evaporative cooling feature selection and classification with relief-F and random forests.

    Science.gov (United States)

    Le, Trang T; Simmons, W Kyle; Misaki, Masaya; Bodurka, Jerzy; White, Bill C; Savitz, Jonathan; McKinney, Brett A

    2017-09-15

    Classification of individuals into disease or clinical categories from high-dimensional biological data with low prediction error is an important challenge of statistical learning in bioinformatics. Feature selection can improve classification accuracy but must be incorporated carefully into cross-validation to avoid overfitting. Recently, feature selection methods based on differential privacy, such as differentially private random forests and reusable holdout sets, have been proposed. However, for domains such as bioinformatics, where the number of features is much larger than the number of observations p≫n , these differential privacy methods are susceptible to overfitting. We introduce private Evaporative Cooling, a stochastic privacy-preserving machine learning algorithm that uses Relief-F for feature selection and random forest for privacy preserving classification that also prevents overfitting. We relate the privacy-preserving threshold mechanism to a thermodynamic Maxwell-Boltzmann distribution, where the temperature represents the privacy threshold. We use the thermal statistical physics concept of Evaporative Cooling of atomic gases to perform backward stepwise privacy-preserving feature selection. On simulated data with main effects and statistical interactions, we compare accuracies on holdout and validation sets for three privacy-preserving methods: the reusable holdout, reusable holdout with random forest, and private Evaporative Cooling, which uses Relief-F feature selection and random forest classification. In simulations where interactions exist between attributes, private Evaporative Cooling provides higher classification accuracy without overfitting based on an independent validation set. In simulations without interactions, thresholdout with random forest and private Evaporative Cooling give comparable accuracies. We also apply these privacy methods to human brain resting-state fMRI data from a study of major depressive disorder. Code

  15. A smartphone "app"-delivered randomized factorial trial targeting physical activity in adults.

    Science.gov (United States)

    Fanning, Jason; Roberts, Sarah; Hillman, Charles H; Mullen, Sean P; Ritterband, Lee; McAuley, Edward

    2017-10-01

    Rapid technological development has challenged researchers developing mobile moderate-to-vigorous physical activity (MVPA) interventions. This 12-week randomized factorial intervention aimed to determine the individual and combined impact of a self-monitoring smartphone-app (tracking, feedback, education) and two theory-based modules (goal-setting, points-based feedback) on MVPA, key psychosocial outcomes, and application usage. Adults (N = 116; M age  = 41.38 ± 7.57) received (1) a basic self-monitoring app, (2) the basic app plus goal setting, (3) the basic app plus points-based feedback, or (4) the basic app plus both modules. All individuals increased MVPA by more than 11 daily minutes. Those with points-based feedback demonstrated still higher levels of MVPA and more favorable psychosocial and app usage outcomes across the intervention. Those with access to in-app goal setting had higher levels of app usage relative to those without the component. It is imperative that effective digital intervention "ingredients" are identified, and these findings provide early evidence to this effect. Trial Registration clinicaltrials.gov identifier NCT02592590.

  16. Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

    Science.gov (United States)

    Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

    2017-09-08

    In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy

  17. Using ArcMap, Google Earth, and Global Positioning Systems to select and locate random households in rural Haiti

    Directory of Open Access Journals (Sweden)

    Wampler Peter J

    2013-01-01

    Full Text Available Abstract Background A remote sensing technique was developed which combines a Geographic Information System (GIS; Google Earth, and Microsoft Excel to identify home locations for a random sample of households in rural Haiti. The method was used to select homes for ethnographic and water quality research in a region of rural Haiti located within 9 km of a local hospital and source of health education in Deschapelles, Haiti. The technique does not require access to governmental records or ground based surveys to collect household location data and can be performed in a rapid, cost-effective manner. Methods The random selection of households and the location of these households during field surveys were accomplished using GIS, Google Earth, Microsoft Excel, and handheld Garmin GPSmap 76CSx GPS units. Homes were identified and mapped in Google Earth, exported to ArcMap 10.0, and a random list of homes was generated using Microsoft Excel which was then loaded onto handheld GPS units for field location. The development and use of a remote sensing method was essential to the selection and location of random households. Results A total of 537 homes initially were mapped and a randomized subset of 96 was identified as potential survey locations. Over 96% of the homes mapped using Google Earth imagery were correctly identified as occupied dwellings. Only 3.6% of the occupants of mapped homes visited declined to be interviewed. 16.4% of the homes visited were not occupied at the time of the visit due to work away from the home or market days. A total of 55 households were located using this method during the 10 days of fieldwork in May and June of 2012. Conclusions The method used to generate and field locate random homes for surveys and water sampling was an effective means of selecting random households in a rural environment lacking geolocation infrastructure. The success rate for locating households using a handheld GPS was excellent and only

  18. Using ArcMap, Google Earth, and Global Positioning Systems to select and locate random households in rural Haiti.

    Science.gov (United States)

    Wampler, Peter J; Rediske, Richard R; Molla, Azizur R

    2013-01-18

    A remote sensing technique was developed which combines a Geographic Information System (GIS); Google Earth, and Microsoft Excel to identify home locations for a random sample of households in rural Haiti. The method was used to select homes for ethnographic and water quality research in a region of rural Haiti located within 9 km of a local hospital and source of health education in Deschapelles, Haiti. The technique does not require access to governmental records or ground based surveys to collect household location data and can be performed in a rapid, cost-effective manner. The random selection of households and the location of these households during field surveys were accomplished using GIS, Google Earth, Microsoft Excel, and handheld Garmin GPSmap 76CSx GPS units. Homes were identified and mapped in Google Earth, exported to ArcMap 10.0, and a random list of homes was generated using Microsoft Excel which was then loaded onto handheld GPS units for field location. The development and use of a remote sensing method was essential to the selection and location of random households. A total of 537 homes initially were mapped and a randomized subset of 96 was identified as potential survey locations. Over 96% of the homes mapped using Google Earth imagery were correctly identified as occupied dwellings. Only 3.6% of the occupants of mapped homes visited declined to be interviewed. 16.4% of the homes visited were not occupied at the time of the visit due to work away from the home or market days. A total of 55 households were located using this method during the 10 days of fieldwork in May and June of 2012. The method used to generate and field locate random homes for surveys and water sampling was an effective means of selecting random households in a rural environment lacking geolocation infrastructure. The success rate for locating households using a handheld GPS was excellent and only rarely was local knowledge required to identify and locate households. This

  19. Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

    Science.gov (United States)

    Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

  20. Going beyond: Target selection and mission analysis of human exploration missions to Near-Earth Asteroids

    Science.gov (United States)

    Zimmer, A. K.; Messerschmid, E.

    2011-12-01

    Missions to Near-Earth Asteroids (NEAs) offer a wide range of possibilities for space exploration, scientific research, and technology demonstration. In particular, manned missions to NEAs provide a unique opportunity to be the first human expedition to an interplanetary body beyond the Earth-Moon system and represent the perfect environment to gain experience in deep-space operations, which is an indispensable prerequisite for human missions to Mars. As a starting point for the analysis of such missions, the objectives of this study are to identify target asteroids and evaluate possible transfer trajectories as well as the associated launch windows. The list of accessible asteroids is narrowed down by taking dynamical and structural properties such as size and rotation rate into account. An accessibility model for NEAs is developed allowing pre-selection of asteroid targets for human missions. For this model, a novel approach is taken which assesses the accessibility of a NEA not by considering its orbital parameters separately. Instead, accessibility is determined by evaluating the combination of all orbital parameters only limited by mission duration (less than 365 days) and round-trip Δv (less than 10 km/s). In order to verify the reliability of the model, mission architectures for missions departing from low-Earth orbit are investigated and transfers to 2567 NEAs in the time frame from 2020 to 2040 are simulated. Two hundred and forty asteroids are found to be accessible for human missions under the given boundary conditions and are observed to nicely fit the model developed. Seventy three of these remaining asteroids can be reached with a Δv≤7.5km/s, 15 of which allow mission durations of less than 200 days. One hundred and seventy launch windows strongly varying in duration are found for these 73 asteroids between 2020 and 2040. Launch opportunity analysis shows that several launch windows open every year in the given time frame for missions with

  1. Selective Targeting of the L858R Mutation (EGFR in Non-Small Cell Lung Cancer: A Mechanism for Advancing Targeted Chemotherapy

    Directory of Open Access Journals (Sweden)

    Rohan Arora

    2017-05-01

    Full Text Available Lung cancer remains one of today’s most deadly and intractable cancers. Non-small cell lung cancer (NSCLC accounts for roughly 85% of lung cancers, with an extremely poor survival rate. To ensure patient comfort and survival, the development of a selective therapy is imperative. However, lung cancer does not display surface proteins associated uniquely with tumor cells; thus, it is very difficult to develop a tumor-specific drug. Current techniques that target overexpression of proteins or inhibit growth pathways are either non-specific or prone to rapid drug resistance. The goal was to design a drug targeted to structural mutations expressed by tumor-associated general surface proteins, thereby combating the lack of tumor-unique markers in lung cancer. Mutant EGFR was identified as a potential target due to its prominence in tumor cells. Due to their size, it was determined that small molecules would be most effective at targeting isolated changes in protein structure, and thereby differentiating between the tumor-associated mutant EGFR and the healthy wild type. Conformational analysis of a virtual binding study conducted in VINA predicted a set of drug-like small molecules specific for the L858R mutation in EGFR. One molecule (ZN47 was then acquired and conjugated to a carrier protein to form a multifaceted hapten–protein conjugate. Multiple ELISAs were conducted to confirm the specificity of the conjugate to both tumor-associated mutant EGFRs. The results indicate that the identified molecule may be highly selective for tumor-associated L858R-EGFR, but further research, including a complete dosage-binding study, is necessary for full validation.

  2. Ets1 identified as a novel molecular target of RNA aptamer selected against metastatic cells for targeted delivery of nano-formulation

    Science.gov (United States)

    Kaur, J; Tikoo, K

    2015-01-01

    Nanomedicine era is not far from its realization, but a major concern of targeted delivery still stands tall in its way. Herein we demonstrate the mechanism underlying the anticancer activity of an RNA aptamer (Apt) conjugated to gefitinib-loaded poly (lactic co-glycolic acid) nanoparticles (GNPs). Apt was selected through Cell-SELEX (systemic evolution of ligands by exponential enrichment) process against gefitinib-resistant H1975 lung cancer cells. The selected aptamer exhibited high specificity toward H1975 cells, both qualitatively as well as quantitatively. Software analysis using the MATCH tool predicted Ets1, a proto-oncoprotein, to be the target of the selected aptamer. Interestingly, the localization of identified aptamer varied in descending order of Ets1 expression, wherein maximum localization was observed in H1975 cells than in MDA-MB231, DU-145, H23, H460, A431, A549 and MCF-7 cells, and minimum in L132 cells. Furthermore, Apt-GNP bio-conjugate showed augmented anticancer activity specifically in Ets1-overexpressing cells. In addition, partial depletion of Ets1 in H1975 cells and overexpression of Ets1 in L132 cells reversed the targeting efficacy of the aptamer. Notably, a single intratumoral injection of the Apt-GNP bio-conjugate abrogated the growth of tumor in H1975 xenograft nude mice. Altogether, we present a pioneering platform, involving aptamers, which can be clinically used as a diagnostic marker for metastasis as well as an effective delivery system to escort the pharmaceutical cargo specifically to Ets1-overexpressing highly progressive tumors. PMID:25639877

  3. Comparing the Selection and Placement of Best Management Practices in Improving Water Quality Using a Multiobjective Optimization and Targeting Method

    Directory of Open Access Journals (Sweden)

    Li-Chi Chiang

    2014-03-01

    Full Text Available Suites of Best Management Practices (BMPs are usually selected to be economically and environmentally efficient in reducing nonpoint source (NPS pollutants from agricultural areas in a watershed. The objective of this research was to compare the selection and placement of BMPs in a pasture-dominated watershed using multiobjective optimization and targeting methods. Two objective functions were used in the optimization process, which minimize pollutant losses and the BMP placement areas. The optimization tool was an integration of a multi-objective genetic algorithm (GA and a watershed model (Soil and Water Assessment Tool—SWAT. For the targeting method, an optimum BMP option was implemented in critical areas in the watershed that contribute the greatest pollutant losses. A total of 171 BMP combinations, which consist of grazing management, vegetated filter strips (VFS, and poultry litter applications were considered. The results showed that the optimization is less effective when vegetated filter strips (VFS are not considered, and it requires much longer computation times than the targeting method to search for optimum BMPs. Although the targeting method is effective in selecting and placing an optimum BMP, larger areas are needed for BMP implementation to achieve the same pollutant reductions as the optimization method.

  4. In vitro HIV-1 selective integration into the target sequence and decoy-effect of the modified sequence.

    Directory of Open Access Journals (Sweden)

    Tatsuaki Tsuruyama

    Full Text Available Although there have been a few reports that the HIV-1 genome can be selectively integrated into the genomic DNA of cultured host cell, the biochemistry of integration selectivity has not been fully understood. We modified the in vitro integration reaction protocol and developed a reaction system with higher efficiency. We used a substrate repeat, 5'-(GTCCCTTCCCAGT(n(ACTGGGAAGGGAC(n-3', and a modified sequence DNA ligated into a circular plasmid. CAGT and ACTG (shown in italics in the above sequence in the repeat units originated from the HIV-1 proviral genome ends. Following the incubation of the HIV-1 genome end cDNA and recombinant integrase for the formation of the pre-integration (PI complex, substrate DNA was reacted with this complex. It was confirmed that the integration selectively occurred in the middle segment of the repeat sequence. In addition, integration frequency and selectivity were positively correlated with repeat number n. On the other hand, both frequency and selectivity decreased markedly when using sequences with deletion of CAGT in the middle position of the original target sequence. Moreover, on incubation with the deleted DNAs and original sequence, the integration efficiency and selectivity for the original target sequence were significantly reduced, which indicated interference effects by the deleted sequence DNAs. Efficiency and selectivity were also found to vary discontinuously with changes in manganese dichloride concentration in the reaction buffer, probably due to its influence on the secondary structure of substrate DNA. Finally, integrase was found to form oligomers on the binding site and substrate DNA formed a loop-like structure. In conclusion, there is a considerable selectivity in HIV-integration into the specified sequence; however, similar DNA sequences can interfere with the integration process, and it is therefore difficult for in vivo integration to occur selectively in the actual host genome DNA.

  5. Targeted HIV Screening in Eight Emergency Departments: The DICI-VIH Cluster-Randomized Two-Period Crossover Trial.

    Science.gov (United States)

    Leblanc, Judith; Hejblum, Gilles; Costagliola, Dominique; Durand-Zaleski, Isabelle; Lert, France; de Truchis, Pierre; Verbeke, Geert; Rousseau, Alexandra; Piquet, Hélène; Simon, François; Pateron, Dominique; Simon, Tabassome; Crémieux, Anne-Claude

    2017-10-30

    This study compares the effectiveness and cost-effectiveness of nurse-driven targeted HIV screening alongside physician-directed diagnostic testing (intervention strategy) with diagnostic testing alone (control strategy) in 8 emergency departments. In this cluster-randomized, 2-period, crossover trial, 18- to 64-year-old patients presenting for reasons other than potential exposure to HIV were included. The strategy applied first was randomly assigned. During both periods, diagnostic testing was prescribed by physicians following usual care. During the intervention periods, patients were asked to complete a self-administered questionnaire. According to their answers, the triage nurse suggested performing a rapid test to patients belonging to a high-risk group. The primary outcome was the proportion of new diagnoses among included patients, which further refers to effectiveness. A secondary outcome was the intervention's incremental cost (health care system perspective) per additional diagnosis. During the intervention periods, 74,161 patients were included, 16,468 completed the questionnaire, 4,341 belonged to high-risk groups, and 2,818 were tested by nurses, yielding 13 new diagnoses. Combined with 9 diagnoses confirmed through 97 diagnostic tests, 22 new diagnoses were established. During the control periods, 74,166 patients were included, 92 were tested, and 6 received a new diagnosis. The proportion of new diagnoses among included patients was higher during the intervention than in the control periods (3.0 per 10,000 versus 0.8 per 10,000; difference 2.2 per 10,000, 95% CI 1.3 to 3.6; relative risk 3.7, 95% CI 1.4 to 9.8). The incremental cost was €1,324 per additional new diagnosis. The combined strategy of targeted screening and diagnostic testing was effective. Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

  6. Random Tagging Genotyping by Sequencing (rtGBS, an Unbiased Approach to Locate Restriction Enzyme Sites across the Target Genome.

    Directory of Open Access Journals (Sweden)

    Elena Hilario

    Full Text Available Genotyping by sequencing (GBS is a restriction enzyme based targeted approach developed to reduce the genome complexity and discover genetic markers when a priori sequence information is unavailable. Sufficient coverage at each locus is essential to distinguish heterozygous from homozygous sites accurately. The number of GBS samples able to be pooled in one sequencing lane is limited by the number of restriction sites present in the genome and the read depth required at each site per sample for accurate calling of single-nucleotide polymorphisms. Loci bias was observed using a slight modification of the Elshire et al.some restriction enzyme sites were represented in higher proportions while others were poorly represented or absent. This bias could be due to the quality of genomic DNA, the endonuclease and ligase reaction efficiency, the distance between restriction sites, the preferential amplification of small library restriction fragments, or bias towards cluster formation of small amplicons during the sequencing process. To overcome these issues, we have developed a GBS method based on randomly tagging genomic DNA (rtGBS. By randomly landing on the genome, we can, with less bias, find restriction sites that are far apart, and undetected by the standard GBS (stdGBS method. The study comprises two types of biological replicates: six different kiwifruit plants and two independent DNA extractions per plant; and three types of technical replicates: four samples of each DNA extraction, stdGBS vs. rtGBS methods, and two independent library amplifications, each sequenced in separate lanes. A statistically significant unbiased distribution of restriction fragment size by rtGBS showed that this method targeted 49% (39,145 of BamH I sites shared with the reference genome, compared to only 14% (11,513 by stdGBS.

  7. ERP markers of target selection discriminate children with high vs. low working memory capacity

    OpenAIRE

    Andria eShimi; Anna Christina eNobre; Gaia eScerif

    2015-01-01

    Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM) system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults’ selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children’s selection of incoming percepts in service of VWM? Do these ...

  8. Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies.

    Science.gov (United States)

    Dheilly, Elie; Moine, Valéry; Broyer, Lucile; Salgado-Pires, Susana; Johnson, Zoë; Papaioannou, Anne; Cons, Laura; Calloud, Sébastien; Majocchi, Stefano; Nelson, Robert; Rousseau, François; Ferlin, Walter; Kosco-Vilbois, Marie; Fischer, Nicolas; Masternak, Krzysztof

    2017-02-01

    CD47 is a ubiquitously expressed immune checkpoint receptor that is often upregulated in cancer. CD47 interacts with its counter-receptor SIRPα on macrophages and other myeloid cells to inhibit cancer cell phagocytosis and drive immune evasion. To overcome tolerability and "antigen sink" issues arising from widespread CD47 expression, we generated dual-targeting bispecific antibodies that selectively block the CD47-SIRPα interaction on malignant cells expressing a specific tumor-associated antigen; e.g., CD19 or mesothelin. These bispecific κλ bodies are fully human, native IgG1 molecules, combining tumor targeting and selective CD47 blockade with immune activating mechanisms mediated by the Fc portion of the antibody. CD47-neutralizing κλ bodies efficiently kill cancer cells in vitro and in vivo but interact only weakly with healthy cells expressing physiological levels of CD47. Accordingly, a κλ body administered to non-human primates showed a typical IgG pharmacokinetic profile and was well tolerated. Importantly, κλ bodies preserve their tumoricidal capabilities in the presence of a CD47 antigen sink. Thus, dual-targeting κλ bodies allow for efficacious yet safe targeting of CD47 in cancer. Such a bispecific design could be applied to limit the extent of neutralization of other ubiquitously expressed therapeutic targets. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. Robust Ground Target Detection by SAR and IR Sensor Fusion Using Adaboost-Based Feature Selection

    National Research Council Canada - National Science Library

    Kim, Sungho; Song, Woo-Jin; Kim, So-Hyun

    2016-01-01

    .... This paper proposes a novel target detection method by decision-level SAR and IR fusion using an Adaboost-based machine learning scheme to achieve a high detection rate and low false alarm rate...

  10. Targeting the Binding Interface on a Shared Receptor Subunit of a Cytokine Family Enables the Inhibition of Multiple Member Cytokines with Selectable Target Spectrum*

    Science.gov (United States)

    Nata, Toshie; Basheer, Asjad; Cocchi, Fiorenza; van Besien, Richard; Massoud, Raya; Jacobson, Steven; Azimi, Nazli; Tagaya, Yutaka

    2015-01-01

    The common γ molecule (γc) is a shared signaling receptor subunit used by six γc-cytokines. These cytokines play crucial roles in the differentiation of the mature immune system and are involved in many human diseases. Moreover, recent studies suggest that multiple γc-cytokines are pathogenically involved in a single disease, thus making the shared γc-molecule a logical target for therapeutic intervention. However, the current therapeutic strategies seem to lack options to treat such cases, partly because of the lack of appropriate neutralizing antibodies recognizing the γc and, more importantly, because of the inherent and practical limitations in the use of monoclonal antibodies. By targeting the binding interface of the γc and cytokines, we successfully designed peptides that not only inhibit multiple γc-cytokines but with a selectable target spectrum. Notably, the lead peptide inhibited three γc-cytokines without affecting the other three or non-γc-cytokines. Biological and mutational analyses of our peptide provide new insights to our current understanding on the structural aspect of the binding of γc-cytokines the γc-molecule. Furthermore, we provide evidence that our peptide, when conjugated to polyethylene glycol to gain stability in vivo, efficiently blocks the action of one of the target cytokines in animal models. Collectively, our technology can be expanded to target various combinations of γc-cytokines and thereby will provide a novel strategy to the current anti-cytokine therapies against immune, inflammatory, and malignant diseases. PMID:26183780

  11. Implementation of Treat-to-Target in Rheumatoid Arthritis Through a Learning Collaborative: Results of a Randomized Controlled Trial.

    Science.gov (United States)

    Solomon, Daniel H; Losina, Elena; Lu, Bing; Zak, Agnes; Corrigan, Cassandra; Lee, Sara B; Agosti, Jenifer; Bitton, Asaf; Harrold, Leslie R; Pincus, Theodore; Radner, Helga; Yu, Zhi; Smolen, Josef S; Fraenkel, Liana; Katz, Jeffrey N

    2017-07-01

    Treat-to-target (TTT) is an accepted paradigm for the management of rheumatoid arthritis (RA), but some evidence suggests poor adherence. The purpose of this study was to test the effects of a group-based multisite improvement learning collaborative on adherence to TTT. We conducted a cluster-randomized quality-improvement trial with waitlist control across 11 rheumatology sites in the US. The intervention entailed a 9-month group-based learning collaborative that incorporated rapid-cycle improvement methods. A composite TTT implementation score was calculated as the percentage of 4 required items documented in the visit notes for each patient at 2 time points, as evaluated by trained staff. The mean change in the implementation score for TTT across all patients for the intervention sites was compared with that for the control sites after accounting for intracluster correlation using linear mixed models. Five sites with a total of 23 participating rheumatology providers were randomized to intervention and 6 sites with 23 participating rheumatology providers were randomized to the waitlist control. The intervention included 320 patients, and the control included 321 patients. At baseline, the mean TTT implementation score was 11% in both arms; after the 9-month intervention, the mean TTT implementation score was 57% in the intervention group and 25% in the control group (change in score of 46% for intervention and 14% for control; P = 0.004). We did not observe excessive use of resources or excessive occurrence of adverse events in the intervention arm. A learning collaborative resulted in substantial improvements in adherence to TTT for the management of RA. This study supports the use of an educational collaborative to improve quality. © 2017, American College of Rheumatology.

  12. Targeted Reminder Phone Calls to Patients at High Risk of No-Show for Primary Care Appointment: A Randomized Trial.

    Science.gov (United States)

    Shah, Sachin J; Cronin, Patrick; Hong, Clemens S; Hwang, Andrew S; Ashburner, Jeffrey M; Bearnot, Benjamin I; Richardson, Calvin A; Fosburgh, Blair W; Kimball, Alexandra B

    2016-12-01

    No-shows, or missed appointments, are a problem for many medical practices. They result in fragmented care and reduce access for all patients. To determine whether telephone reminder calls targeted to patients at high risk of no-show can reduce no-show rates. Single-center randomized controlled trial. A total of 2247 primary care patients in a hospital-based primary care clinic at high risk of no-show (>15 % risk) for their appointment in 7 days. Seven days prior to their appointment, intervention arm patients were placed in a calling queue to receive a reminder phone call from a patient service coordinator. Coordinators were trained to engage patients in concrete planning. All patients received an automated phone call (usual care). Primary outcome was no-show rate. Secondary outcomes included arrival rate, cancellation rate, reschedule rate, time to cancellation, and change in revenue. The no-show rate in the intervention arm (22.8 %) was significantly lower (absolute risk difference -6.4 %, p phone call 7 days prior to an appointment led to a significant reduction in no-shows and increased reimbursement among patients at high risk of no-show. The use of targeted interventions may be of interest to practices taking on increased accountability for population health.

  13. Investigation on wide-band scattering of a 2-D target above 1-D randomly rough surface by FDTD method.

    Science.gov (United States)

    Li, Juan; Guo, Li-Xin; Jiao, Yong-Chang; Li, Ke

    2011-01-17

    Finite-difference time-domain (FDTD) algorithm with a pulse wave excitation is used to investigate the wide-band composite scattering from a two-dimensional(2-D) infinitely long target with arbitrary cross section located above a one-dimensional(1-D) randomly rough surface. The FDTD calculation is performed with a pulse wave incidence, and the 2-D representative time-domain scattered field in the far zone is obtained directly by extrapolating the currently calculated data on the output boundary. Then the 2-D wide-band scattering result is acquired by transforming the representative time-domain field to the frequency domain with a Fourier transform. Taking the composite scattering of an infinitely long cylinder above rough surface as an example, the wide-band response in the far zone by FDTD with the pulsed excitation is computed and it shows a good agreement with the numerical result by FDTD with the sinusoidal illumination. Finally, the normalized radar cross section (NRCS) from a 2-D target above 1-D rough surface versus the incident frequency, and the representative scattered fields in the far zone versus the time are analyzed in detail.

  14. SPIDERS: selection of spectroscopic targets using AGN candidates detected in all-sky X-ray surveys

    Science.gov (United States)

    Dwelly, T.; Salvato, M.; Merloni, A.; Brusa, M.; Buchner, J.; Anderson, S. F.; Boller, Th.; Brandt, W. N.; Budavári, T.; Clerc, N.; Coffey, D.; Del Moro, A.; Georgakakis, A.; Green, P. J.; Jin, C.; Menzel, M.-L.; Myers, A. D.; Nandra, K.; Nichol, R. C.; Ridl, J.; Schwope, A. D.; Simm, T.

    2017-07-01

    SPIDERS (SPectroscopic IDentification of eROSITA Sources) is a Sloan Digital Sky Survey IV (SDSS-IV) survey running in parallel to the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) cosmology project. SPIDERS will obtain optical spectroscopy for large numbers of X-ray-selected active galactic nuclei (AGN) and galaxy cluster members detected in wide-area eROSITA, XMM-Newton and ROSAT surveys. We describe the methods used to choose spectroscopic targets for two sub-programmes of SPIDERS X-ray selected AGN candidates detected in the ROSAT All Sky and the XMM-Newton Slew surveys. We have exploited a Bayesian cross-matching algorithm, guided by priors based on mid-IR colour-magnitude information from the Wide-field Infrared Survey Explorer survey, to select the most probable optical counterpart to each X-ray detection. We empirically demonstrate the high fidelity of our counterpart selection method using a reference sample of bright well-localized X-ray sources collated from XMM-Newton, Chandra and Swift-XRT serendipitous catalogues, and also by examining blank-sky locations. We describe the down-selection steps which resulted in the final set of SPIDERS-AGN targets put forward for spectroscopy within the eBOSS/TDSS/SPIDERS survey, and present catalogues of these targets. We also present catalogues of ˜12 000 ROSAT and ˜1500 XMM-Newton Slew survey sources that have existing optical spectroscopy from SDSS-DR12, including the results of our visual inspections. On completion of the SPIDERS programme, we expect to have collected homogeneous spectroscopic redshift information over a footprint of ˜7500 deg2 for >85 per cent of the ROSAT and XMM-Newton Slew survey sources having optical counterparts in the magnitude range 17 < r < 22.5, producing a large and highly complete sample of bright X-ray-selected AGN suitable for statistical studies of AGN evolution and clustering.

  15. Effectiveness of a selective alcohol prevention program targeting personality risk factors : Results of interaction analyses

    NARCIS (Netherlands)

    Lammers, J.; Goossens, F.; Conrod, P.; Engels, R.; Wiers, R.W.; Kleinjan, M.

    AIM: To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. DESIGN: A clustered randomized controlled trial, with

  16. Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses

    NARCIS (Netherlands)

    Lammers, J.; Goossens, F.; Conrod, P.; Engels, R.C.M.E.; Wiers, R.W.H.J.; Kleinjan, M.

    2017-01-01

    Aim: To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. Design: A clustered randomized controlled trial, with

  17. Targeted Multifunctional Nanoparticles cure and image Brain Tumors: Selective MRI Contrast Enhancement and Photodynamic Therapy

    Science.gov (United States)

    Kopelman, Raoul

    2008-03-01

    Aimed at targeted therapy and imaging of brain tumors, our approach uses targeted, multi-functional nano-particles (NP). A typical nano-particle contains a biologically inert, non-toxic matrix, biodegradable and bio-eliminable over a long time period. It also contains active components, such as fluorescent chemical indicators, photo-sensitizers, MRI contrast enhancement agents and optical imaging dyes. In addition, its surface contains molecular targeting units, e.g. peptides or antibodies, as well as a cloaking agent, to prevent uptake by the immune system, i.e. enabling control of the plasma residence time. These dynamic nano-platforms (DNP) contain contrast enhancement agents for the imaging (MRI, optical, photo-acoustic) of targeted locations, i.e. tumors. Added to this are targeted therapy agents, such as photosensitizers for photodynamic therapy (PDT). A simple protocol, for rats implanted with human brain cancer, consists of tail injection with DNPs, followed by 5 min red light illumination of the tumor region. It resulted in excellent cure statistics for 9L glioblastoma.

  18. A computational tool to optimize ligand selectivity between two similar biomacromolecular targets

    Science.gov (United States)

    Chen, Deliang L.; Kellogg, Glen E.

    2005-02-01

    Algorithms for a new computer program designed to increase ligand-receptor selectivity between two proteins are described. In this program ligand-receptor selectivity is increased by functional modifications to the ligand so as to increase the calculated binding affinity of it to one protein and/or decrease the calculated binding affinity of it to the other protein. The structure of the ligand is modified by selective replacement of atoms and/or functional groups in silico based on a specific set of steric and/or hydropathic complementarity rules involving atoms and functional groups. Relative binding scores are calculated with simple grid-based steric penalty, hydrogen bond complementarity, and with the HINT score model. Two examples are shown. First, modifying the structure of the ligand CB3717 is illustrated in a number of ways such that the binding selectivity to wild type L. casei thymidylate synthase or its E60Q mutant may be improved. Second, starting with a non-selective lead compound that had been co-crystallized with both plant and mammalian 4-hydroxyphenylpyruvate dioxygenases, new compounds (similar to selective ligands discovered by screening) to improve the selectivity of (herbicidal) inhibitors for the plant enzyme were designed by the program.

  19. ERP markers of target selection discriminate children with high vs. low working memory capacity

    Directory of Open Access Journals (Sweden)

    Andria eShimi

    2015-11-01

    Full Text Available Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults’ selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children’s selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults’ selection? Ten-year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc. However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the adult time-window related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children’s neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM

  20. ERP markers of target selection discriminate children with high vs. low working memory capacity.

    Science.gov (United States)

    Shimi, Andria; Nobre, Anna Christina; Scerif, Gaia

    2015-01-01

    Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM) system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults' selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children's selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults' selection? Ten-year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc). However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the "adult time-window" related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children's neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM performance in children.

  1. Use of mathematics to guide target selection in systems pharmacology; application to receptor tyrosine kinase (RTK) pathways.

    Science.gov (United States)

    Benson, Neil; van der Graaf, Piet H; Peletier, Lambertus A

    2017-05-24

    A key element of the drug discovery process is target selection. Although the topic is subject to much discussion and experimental effort, there are no defined quantitative rules around optimal selection. Often 'rules of thumb', that have not been subject to rigorous exploration, are used. In this paper we explore the 'rule of thumb' notion that the molecule that initiates a pathway signal is the optimal target. Given the multi-factorial and complex nature of this question, we have simplified an example pathway to its logical minimum of two steps and used a mathematical model of this to explore the different options in the context of typical small and large molecule drugs. In this paper, we report the conclusions of our analysis and describe the analysis tool and methods used. These provide a platform to enable a more extensive enquiry into this important topic. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression

    DEFF Research Database (Denmark)

    Ravnskjær, Kim; Kester, Henri; Liu, Yi

    2007-01-01

    A number of hormones and growth factors stimulate gene expression by promoting the phosphorylation of CREB (P-CREB), thereby enhancing its association with the histone acetylase paralogs p300 and CBP (CBP/p300). Relative to cAMP, stress signals trigger comparable amounts of CREB phosphorylation......, but have minimal effects on CRE-dependent transcription. Here, we show that the latent cytoplasmic coactivator TORC2 mediates target gene activation in response to cAMP signaling by associating with CBP/p300 and increasing its recruitment to a subset of CREB target genes. TORC2 is not activated in response......-mediated transcription in cells exposed to stress signals. Taken together, these results indicate that TORC2 is one of the long sought after cofactors that mediates the differential effects of cAMP and stress pathways on CREB target gene expression....

  3. The basic science and mathematics of random mutation and natural selection.

    Science.gov (United States)

    Kleinman, Alan

    2014-12-20

    The mutation and natural selection phenomenon can and often does cause the failure of antimicrobial, herbicidal, pesticide and cancer treatments selection pressures. This phenomenon operates in a mathematically predictable behavior, which when understood leads to approaches to reduce and prevent the failure of the use of these selection pressures. The mathematical behavior of mutation and selection is derived using the principles given by probability theory. The derivation of the equations describing the mutation and selection phenomenon is carried out in the context of an empirical example. Copyright © 2014 John Wiley & Sons, Ltd.

  4. Tetrahydro-2-naphthyl and 2-Indanyl Triazolopyrimidines Targeting Plasmodium falciparum Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

    OpenAIRE

    Kokkonda, Sreekanth; Deng, Xiaoyi; White, Karen L.; Coteron, Jose M.; Marco, Maria; de las Heras, Laura; White, John; El Mazouni, Farah; Tomchick, Diana R.; Manjalanagara, Krishne; Rudra, Kakali Rani; Chen, Gong; Morizzi, Julia; Ryan, Eileen; Kaminsky, Werner

    2016-01-01

    Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor 1 (DSM265) is in clinical development. We sought to identify compounds with higher potency against Plasmodium DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the p-SF5-anili...

  5. Selective recognition and stabilization of new ligands targeting the potassium form of the human telomeric G-quadruplex DNA

    Science.gov (United States)

    Lin, Yi-Hwa; Chuang, Show-Mei; Wu, Pei-Ching; Chen, Chun-Liang; Jeyachandran, Sivakamavalli; Lo, Shou-Chen; Huang, Hsu-Shan; Hou, Ming-Hon

    2016-08-01

    The development of a ligand that is capable of distinguishing among the wide variety of G-quadruplex structures and targeting telomeres to treat cancer is particularly challenging. In this study, the ability of two anthraquinone telomerase inhibitors (NSC749235 and NSC764638) to target telomeric G-quadruplex DNA was probed. We found that these ligands specifically target the potassium form of telomeric G-quadruplex DNA over the DNA counterpart. The characteristic interaction with the telomeric G-quadruplex DNA and the anticancer activities of these ligands were also explored. The results of this present work emphasize our understanding of the binding selectivity of anthraquinone derivatives to G-quadruplex DNA and assists in future drug development for G-quadruplex-specific ligands.

  6. K-targeted metabolomic analysis extends chemical subtraction to DESIGNER extracts: selective depletion of extracts of hops (Humulus lupulus).

    Science.gov (United States)

    Ramos Alvarenga, René F; Friesen, J Brent; Nikolić, Dejan; Simmler, Charlotte; Napolitano, José G; van Breemen, Richard; Lankin, David C; McAlpine, James B; Pauli, Guido F; Chen, Shao-Nong

    2014-12-26

    This study introduces a flexible and compound targeted approach to Deplete and Enrich Select Ingredients to Generate Normalized Extract Resources, generating DESIGNER extracts, by means of chemical subtraction or augmentation of metabolites. Targeting metabolites based on their liquid-liquid partition coefficients (K values), K targeting uses countercurrent separation methodology to remove single or multiple compounds from a chemically complex mixture, according to the following equation: DESIGNER extract = total extract ± target compound(s). Expanding the scope of the recently reported depletion of extracts by immunoaffinity or solid phase liquid chromatography, the present approach allows a more flexible, single- or multi-targeted removal of constituents from complex extracts such as botanicals. Chemical subtraction enables both chemical and biological characterization, including detection of synergism/antagonism by both the subtracted targets and the remaining metabolite mixture, as well as definition of the residual complexity of all fractions. The feasibility of the DESIGNER concept is shown by K-targeted subtraction of four bioactive prenylated phenols, isoxanthohumol (1), 8-prenylnaringenin (2), 6-prenylnaringenin (3), and xanthohumol (4), from a standardized hops (Humulus lupulus L.) extract using specific solvent systems. Conversely, adding K-targeted isolates allows enrichment of the original extract and hence provides an augmented DESIGNER material. Multiple countercurrent separation steps were used to purify each of the four compounds, and four DESIGNER extracts with varying depletions were prepared. The DESIGNER approach innovates the characterization of chemically complex extracts through integration of enabling technologies such as countercurrent separation, K-by-bioactivity, the residual complexity concepts, as well as quantitative analysis by (1)H NMR, LC-MS, and HiFSA-based NMR fingerprinting.

  7. Common Risk Alleles for Inflammatory Diseases Are Targets of Recent Positive Selection

    Science.gov (United States)

    Raj, Towfique; Kuchroo, Manik; Replogle, Joseph M.; Raychaudhuri, Soumya; Stranger, Barbara E.; De Jager, Philip L.

    2013-01-01

    Genome-wide association studies (GWASs) have identified hundreds of loci harboring genetic variation influencing inflammatory-disease susceptibility in humans. It has been hypothesized that present day inflammatory diseases may have arisen, in part, due to pleiotropic effects of host resistance to pathogens over the course of human history, with significant selective pressures acting to increase host resistance to pathogens. The extent to which genetic factors underlying inflammatory-disease susceptibility has been influenced by selective processes can now be quantified more comprehensively than previously possible. To understand the evolutionary forces that have shaped inflammatory-disease susceptibility and to elucidate functional pathways affected by selection, we performed a systems-based analysis to integrate (1) published GWASs for inflammatory diseases, (2) a genome-wide scan for signatures of positive selection in a population of European ancestry, (3) functional genomics data comprised of protein-protein interaction networks, and (4) a genome-wide expression quantitative trait locus (eQTL) mapping study in peripheral blood mononuclear cells (PBMCs). We demonstrate that loci for inflammatory-disease susceptibility are enriched for genomic signatures of recent positive natural selection, with selected loci forming a highly interconnected protein-protein interaction network. Further, we identify 21 loci for inflammatory-disease susceptibility that display signatures of recent positive selection, of which 13 also show evidence of cis-regulatory effects on genes within the associated locus. Thus, our integrated analyses highlight a set of susceptibility loci that might subserve a shared molecular function and has experienced selective pressure over the course of human history; today, these loci play a key role in influencing susceptibility to multiple different inflammatory diseases, in part through alterations of gene expression in immune cells. PMID:23522783

  8. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial.

    Science.gov (United States)

    Howard, Barbara V; Roman, Mary J; Devereux, Richard B; Fleg, Jerome L; Galloway, James M; Henderson, Jeffrey A; Howard, Wm James; Lee, Elisa T; Mete, Mihriye; Poolaw, Bryce; Ratner, Robert E; Russell, Marie; Silverman, Angela; Stylianou, Mario; Umans, Jason G; Wang, Wenyu; Weir, Matthew R; Weissman, Neil J; Wilson, Charlton; Yeh, Fawn; Zhu, Jianhui

    2008-04-09

    Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested. To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower. A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events. Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both. Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events. Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P

  9. Highly stable aptamers selected from a 2'-fully modified fGmH RNA library for targeting biomaterials.

    Science.gov (United States)

    Friedman, Adam D; Kim, Dongwook; Liu, Rihe

    2015-01-01

    When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2' modification. This study aims to develop a novel class of highly stable, 2'-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2'-F-dG, 2'-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2'-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and specifically deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials.

  10. Engineering and Selection of Shuffled AAV Genomes: A New Strategy for Producing Targeted Biological Nanoparticles

    OpenAIRE

    Li, Wuping; Asokan, Aravind; Wu, Zhijian; Van Dyke, Terry; DiPrimio, Nina; Johnson, Jarrod S.; Govindaswamy, Lakshmanan; Agbandje-McKenna, Mavis; Leichtle, Stefan; Eugene Redmond Jr, D; McCown, Thomas J; Petermann, Kimberly B; Sharpless, Norman E.; Samulski, Richard J.

    2008-01-01

    We report a DNA shuffling–based approach for developing cell type–specific vectors through directed evolution. Capsid genomes of adeno-associated virus (AAV) serotypes 1–9 were randomly fragmented and reassembled using PCR to generate a chimeric capsid library. A single infectious clone (chimeric-1829) containing genome fragments from AAV1, 2, 8, and 9 was isolated from an integrin minus hamster melanoma cell line previously shown to have low permissiveness to AAV. Molecular modeling studies ...

  11. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin...

  12. Target Selection by the Frontal Cortex during Coordinated Saccadic and Smooth Pursuit Eye Movements

    Science.gov (United States)

    Srihasam, Krishna; Bullock, Daniel; Grossberg, Stephen

    2009-01-01

    Oculomotor tracking of moving objects is an important component of visually based cognition and planning. Such tracking is achieved by a combination of saccades and smooth-pursuit eye movements. In particular, the saccadic and smooth-pursuit systems interact to often choose the same target, and to maximize its visibility through time. How do…

  13. Selective targeting of pentoxifylline platinum-based to hepatic stellate cells using a novel linker technology

    NARCIS (Netherlands)

    Gonzalo, T; Talman, EG; de Ven, AV; Temming, K; Greupink, R; Beljaars, L; Reker-Smit, C; Meijer, DKF; Molema, G; Poelstra, K; Kok, RJ

    2006-01-01

    Targeting of antifibrotic drugs to hepatic stellate cells (HSC) is a promising strategy to block fibrotic processes leading to liver cirrhosis. For this purpose, we utilized the neo-glycoprotein mannose-6-phosphate-albumin (M6PHSA) that accumulates efficiently in HSC during liver fibrosis.

  14. A selective neurokinin-1 receptor antagonist in chronic PTSD: a randomized, double-blind, placebo-controlled, proof-of-concept trial.

    Science.gov (United States)

    Mathew, Sanjay J; Vythilingam, Meena; Murrough, James W; Zarate, Carlos A; Feder, Adriana; Luckenbaugh, David A; Kinkead, Becky; Parides, Michael K; Trist, David G; Bani, Massimo S; Bettica, Paolo U; Ratti, Emiliangelo M; Charney, Dennis S

    2011-03-01

    The substance P-neurokinin-1 receptor (SP-NK(1)R) system has been extensively studied in experimental models of stress, fear, and reward. Elevated cerebrospinal fluid (CSF) SP levels were reported previously in combat-related PTSD. No medication specifically targeting this system has been tested in PTSD. This proof-of-concept randomized, double-blind, placebo-controlled trial evaluated the selective NK(1)R antagonist GR205171 in predominately civilian PTSD. Following a 2-week placebo lead-in, 39 outpatients with chronic PTSD and a Clinician-Administered PTSD Scale (CAPS) score ≥50 were randomized to a fixed dose of GR205171 (N=20) or placebo (N=19) for 8weeks. The primary endpoint was mean change from baseline to endpoint in the total CAPS score. Response rate (≥50% reduction in baseline CAPS) and safety/tolerability were secondary endpoints. CSF SP concentrations were measured in a subgroup of patients prior to randomization. There was significant improvement in the mean CAPS total score across all patients over time, but no significant difference was found between GR205171 and placebo. Likewise, there was no significant effect of drug on the proportion of responders [40% GR205171 versus 21% placebo (p=0.30)]. An exploratory analysis showed that GR205171 treatment was associated with significant improvement compared to placebo on the CAPS hyperarousal symptom cluster. GR205171 was well-tolerated, with no discontinuations due to adverse events. CSF SP concentrations were positively correlated with baseline CAPS severity. The selective NK(1)R antagonist GR205171 had fewer adverse effects but was not significantly superior to placebo in the short-term treatment of chronic PTSD. (ClinicalTrials.gov Identifier: NCT 00211861, NCT 00383786). Published by Elsevier B.V.

  15. Selection and Characterization of Single Chain Antibody Fragments Specific for Hsp90 as a Potential Cancer Targeting Molecule

    Directory of Open Access Journals (Sweden)

    Edyta Petters

    2015-08-01

    Full Text Available Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer therapeutic approaches. The potential and importance of Hsp90-directed agents becomes apparent when one realizes that disruption of Hsp90 function may influence over 200 oncogenic client proteins. Here, we described the selection and characterization of Hsp90-specific antibody fragments from commercially available Tomlinson I and J phage display libraries. The affinities of Hsp90-binding scFv variants were measured using SPR method. Then, based on the best clone selected, we performed the affinity maturation procedure and obtained valuable Hsp90-specific clones. The selected binders were expressed and applied for immunostaining, ELISA and SPR analysis using model cancer cell lines. All performed experiments confirmed the ability of selected antibodies to interact with the Hsp90. Therefore, the presented Hsp90-specific scFv, might be a starting point for the development of a novel antibody-based strategy targeting cancer.

  16. Screen-time Weight-loss Intervention Targeting Children at Home (SWITCH: A randomized controlled trial study protocol

    Directory of Open Access Journals (Sweden)

    Tsai Midi

    2011-06-01

    Full Text Available Abstract Background Approximately one third of New Zealand children and young people are overweight or obese. A similar proportion (33% do not meet recommendations for physical activity, and 70% do not meet recommendations for screen time. Increased time being sedentary is positively associated with being overweight. There are few family-based interventions aimed at reducing sedentary behavior in children. The aim of this trial is to determine the effects of a 24 week home-based, family oriented intervention to reduce sedentary screen time on children's body composition, sedentary behavior, physical activity, and diet. Methods/Design The study design is a pragmatic two-arm parallel randomized controlled trial. Two hundred and seventy overweight children aged 9-12 years and primary caregivers are being recruited. Participants are randomized to intervention (family-based screen time intervention or control (no change. At the end of the study, the control group is offered the intervention content. Data collection is undertaken at baseline and 24 weeks. The primary trial outcome is child body mass index (BMI and standardized body mass index (zBMI. Secondary outcomes are change from baseline to 24 weeks in child percentage body fat; waist circumference; self-reported average daily time spent in physical and sedentary activities; dietary intake; and enjoyment of physical activity and sedentary behavior. Secondary outcomes for the primary caregiver include change in BMI and self-reported physical activity. Discussion This study provides an excellent example of a theory-based, pragmatic, community-based trial targeting sedentary behavior in overweight children. The study has been specifically designed to allow for estimation of the consistency of effects on body composition for Māori (indigenous, Pacific and non-Māori/non-Pacific ethnic groups. If effective, this intervention is imminently scalable and could be integrated within existing weight

  17. Multifactorial assessment and targeted intervention in nutritional status among the older adults: a randomized controlled trial: the Octabaix study.

    Science.gov (United States)

    Badia, Teresa; Formiga, Francesc; Ferrer, Assumpta; Sanz, Héctor; Hurtos, Laura; Pujol, Ramón

    2015-04-11

    Malnutrition is frequent among older people and is associated with morbi-mortality. The aim of the study is to assess the effectiveness of a multifactorial and multidisciplinary intervention in the nutritional status among the elderly. Randomized, single-blind, parallel-group, clinical trial conducted from January 2009 to December 2010 in seven primary health care centers in Baix Llobregat (Barcelona). Of 696 referred people, born in 1924, 328 subjects were randomized to an intervention group or a control group. The intervention model used an algorithm and was multifaceted for both the patients and their primary care providers. The main outcome was improvement in nutritional status assessed by Mini Nutritional Assessment (MNA). Data analyses were done by intention-to-treat. Two-year assessment was completed for 127 patients (77.4%) in the intervention group and 98 patients (59.7%) in the control group. In the adjusted linear mixed models for MNA, intervention showed no significant effect during all follow-up period with -0.21 (CI: - 0.96; 0.26). In subjects with nutritional risk (MNA ≤ 23.5/30) existed a tendency towards improvement in MNA score 1.13 (95% CI -0.48; 2.74) after 2 years. A universal multifactorial assessment and target intervention over a two year period in subjects at nutritional risk showed a tendency to improve nutrition but not in the rest of community-dwelling studied subjects. Cognitive impairment was an independent factor strongly associated with a decline in nutritional status. The clinical trial is registered as part of a US National Institutes of Health Clinical Trial: NCT01141166.

  18. Classifier-based offline feature selection and evaluation for visual tracking of sea-surface and aerial targets

    Science.gov (United States)

    Çakır, Serdar; Aytaç, Tayfun; Yıldırım, Alper; Gerek, Ö. Nezih

    2011-10-01

    An offline feature selection and evaluation mechanism is used in order to develop a robust visual tracking scheme for sea-surface and aerial targets. The covariance descriptors, known to constitute an efficient signature set in object detection and classification problems, are used in the feature extraction phase of the proposed scheme. The performance of feature sets are compared using support vector machines, and those resulting in the highest detection performance are used in the covariance based tracker. The tracking performance is evaluated in different scenarios using different performance measures with respect to ground truth target positions. The proposed tracking scheme is observed to track sea-surface and aerial targets with plausible accuracies, and the results show that gradient-based features, together with the pixel locations and intensity values, provide robust target tracking in both surveillance scenarios. The performance of the proposed tracking strategy is also compared with some well-known trackers including correlation, Kanade-Lucas-Tomasi feature, and scale invariant feature transform-based trackers. Experimental results and observations show that the proposed target tracking scheme outperforms other trackers in both air and sea surveillance scenarios.

  19. Target guided synthesis using DNA nano-templates for selectively assembling a G-quadruplex binding c-MYC inhibitor

    Science.gov (United States)

    Panda, Deepanjan; Saha, Puja; Das, Tania; Dash, Jyotirmayee

    2017-07-01

    The development of small molecules is essential to modulate the cellular functions of biological targets in living system. Target Guided Synthesis (TGS) approaches have been used for the identification of potent small molecules for biological targets. We herein demonstrate an innovative example of TGS using DNA nano-templates that promote Huisgen cycloaddition from an array of azide and alkyne fragments. A G-quadruplex and a control duplex DNA nano-template have been prepared by assembling the DNA structures on gold-coated magnetic nanoparticles. The DNA nano-templates facilitate the regioselective formation of 1,4-substituted triazole products, which are easily isolated by magnetic decantation. The G-quadruplex nano-template can be easily recovered and reused for five reaction cycles. The major triazole product, generated by the G-quadruplex inhibits c-MYC expression by directly targeting the c-MYC promoter G-quadruplex. This work highlights that the nano-TGS approach may serve as a valuable strategy to generate target-selective ligands for drug discovery.

  20. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  1. Variable selection for confounder control, flexible modeling and Collaborative Targeted Minimum Loss-based Estimation in causal inference

    Science.gov (United States)

    Schnitzer, Mireille E.; Lok, Judith J.; Gruber, Susan

    2015-01-01

    This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low-and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios. PMID:26226129

  2. Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening

    Science.gov (United States)

    Abrahams, Garth L.; Kumar, Anuradha; Savvi, Suzana; Hung, Alvin W.; Wen, Shijun; Abell, Chris; Barry, Clifton E.; Sherman, David R.; Boshoff, Helena I.M.; Mizrahi, Valerie

    2012-01-01

    SUMMARY Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery but subsequent target elucidation often proves difficult. Conditional mutants that under-express essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA) and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered the mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. PMID:22840772

  3. Manual versus target-controlled infusion of balanced propofol during diagnostic colonoscopy: A prospective randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Vučićević Vera

    2016-01-01

    Full Text Available Introduction. There is an increasing interest in balanced propofol sedation (BPS for colonoscopy in outpatient settings. Propofol is a potent anesthetic agent for this purpose and has a narrow therapeutic range, which increases a risk of cardiovascular and respiratory complications in case of improper administration. Objective. The aim of this study was to compare patients’ safety and comfort of endoscopists in two methods of BPS targeting deep sedation - propofol target-controlled infusion (TCI and manual intravenous titration technique (MT - during colonoscopy. Methods. This prospective randomized controlled trial included 90 patients (class I or II of the American Society of Anesthesiologists deeply sedated with propofol, coadministered with small doses of midazolam and fentanyl. Propofol was given by MT technique (45 patients or by TCI (45 patients. The following adverse effects were recorded: hypotension, hypertension, bradycardia, tachycardia, hypoxemia, bradypnea, apnea, hiccupping, and coughing, as well as endoscopist’s comfort during colonoscopy by means of a questionnaire. Results. The MT group compared to the TCI group had a lower mean arterial pressure in the 10th minute after the beginning (p = 0.017, and at the end of colonoscopy (p = 0.006, higher oxygen saturation in the fifth minute (p = 0.033, and in the 15th minute (p = 0.008 after the beginning of colonoscopy, and lower heart rate at the beginning of the procedure (p = 0.001. There were no statistically significant differences in adverse events. Endoscopist’s comfort during colonoscopy was high 95.6% in the TCI group vs. 88.9% in the MT group (p = 0.069. Conclusion. MT is clinically as stable as TCI of propofol for deep sedation during colonoscopy, and endoscopists experienced the same comfort during colonoscopy in both groups. Thus, both combinations are suitable for deep sedation during diagnostic colonoscopy.

  4. Prevention of colitis-associated cancer by selective targeting of immunoproteasome subunit LMP7

    DEFF Research Database (Denmark)

    Vachharajani, Niyati; Joeris, Thorsten; Luu, Maik

    2017-01-01

    , the deletion or pharmacological inhibition of LMP7 and consequent blockade of NF-κB abrogated the production of IL-17A, which possesses a strong carcinogenic activity in the gut. Moreover, in vivo administration of the selective LMP7 inhibitor ONX-0914 led to a marked reduction of tumor numbers in wild...

  5. Targeting hunter distribution based on host resource selection and kill sites to manage disease risk

    DEFF Research Database (Denmark)

    Dugal, Cherie; van Beest, Floris; Vander Wal, Eric

    2013-01-01

    , in southwestern Manitoba, Canada. Distance to protected area was the most important covariate influencing resource selection and hunter-kill sites of elk (AICw = 1.00). Collared adult males (which are most likely to be infected with bovine tuberculosis (Mycobacterium bovis) and chronic wasting disease) rarely...

  6. Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma

    NARCIS (Netherlands)

    Tummers, W.S. (Willemieke S.); A. Fariña-Sarasqueta (Arantza); M.C. Boonstra (M.); Prevoo, H.A. (Hendrica A.); C.F.M. Sier (Cornelis); J.S.D. Mieog (Sven); H. Morreau (Hans); C.H.J. van Eijck (Casper); P.J.K. Kuppen (P. J K); C.J.H. van de Velde (Cornelis); B.A. Bonsing (Bert); A.L. Vahrmeijer (Alexander L.); Swijnenburg, R.-J. (Rutger-Jan)

    2017-01-01

    textabstractDiscrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this

  7. Design of an EGFR-targeting toxin for photochemical delivery: in vitro and in vivo selectivity and efficacy.

    Science.gov (United States)

    Berstad, M B; Cheung, L H; Berg, K; Peng, Q; Fremstedal, A S V; Patzke, S; Rosenblum, M G; Weyergang, A

    2015-10-29

    The number of epidermal growth factor receptor (EGFR)-targeting drugs in the development for cancer treatment is continuously increasing. Currently used EGFR-targeted monoclonal antibodies and tyrosine kinase inhibitors have specific limitations related to toxicity and development of resistance, and there is a need for alternative treatment strategies to maximize the clinical potential of EGFR as a molecular target. This study describes the design and production of a novel EGFR-targeted fusion protein, rGel/EGF, composed of the recombinant plant toxin gelonin and EGF. rGel/EGF was custom-made for administration by photochemical internalization (PCI), a clinically tested modality for cytosolic release of macromolecular therapeutics. rGel/EGF lacks efficient mechanisms for endosomal escape and is therefore minimally toxic as monotherapy. However, PCI induces selective and efficient cytosolic release of rGel/EGF in EGFR-expressing target cells by light-directed activation of photosensitizers accumulated selectively in tumor tissue. PCI of rGel/EGF was shown to be highly effective against EGFR-expressing cell lines, including head and neck squamous cell carcinoma (HNSCC) cell lines resistant to cetuximab (Erbitux). Apoptosis, necrosis and autophagy were identified as mechanisms of action following PCI of rGel/EGF in vitro. PCI of rGel/EGF was further shown as a highly tumor-specific and potent modality in vivo, with growth inhibitory effects demonstrated on A-431 squamous cell carcinoma (SCC) xenografts and reduction of tumor perfusion and necrosis induction in SCC-026 HNSCC tumors. Considering the small amount of rGel/EGF injected per animal (0.1 mg/kg), the presented in vivo results are highly promising and warrant optimization and production of rGel/EGF for further preclinical evaluation with PCI.

  8. The Jackprot Simulation Couples Mutation Rate with Natural Selection to Illustrate How Protein Evolution Is Not Random

    Science.gov (United States)

    Espinosa, Avelina; Bai, Chunyan Y.

    2016-01-01

    Protein evolution is not a random process. Views which attribute randomness to molecular change, deleterious nature to single-gene mutations, insufficient geological time, or population size for molecular improvements to occur, or invoke “design creationism” to account for complexity in molecular structures and biological processes, are unfounded. Scientific evidence suggests that natural selection tinkers with molecular improvements by retaining adaptive peptide sequence. We used slot-machine probabilities and ion channels to show biological directionality on molecular change. Because ion channels reside in the lipid bilayer of cell membranes, their residue location must be in balance with the membrane's hydrophobic/philic nature; a selective “pore” for ion passage is located within the hydrophobic region. We contrasted the random generation of DNA sequence for KcsA, a bacterial two-transmembrane-domain (2TM) potassium channel, from Streptomyces lividans, with an under-selection scenario, the “jackprot,” which predicted much faster evolution than by chance. We wrote a computer program in JAVA APPLET version 1.0 and designed an online interface, The Jackprot Simulation http://faculty.rwu.edu/cbai/JackprotSimulation.htm, to model a numerical interaction between mutation rate and natural selection during a scenario of polypeptide evolution. Winning the “jackprot,” or highest-fitness complete-peptide sequence, required cumulative smaller “wins” (rewarded by selection) at the first, second, and third positions in each of the 161 KcsA codons (“jackdons” that led to “jackacids” that led to the “jackprot”). The “jackprot” is a didactic tool to demonstrate how mutation rate coupled with natural selection suffices to explain the evolution of specialized proteins, such as the complex six-transmembrane (6TM) domain potassium, sodium, or calcium channels. Ancestral DNA sequences coding for 2TM-like proteins underwent nucleotide

  9. The Jackprot Simulation Couples Mutation Rate with Natural Selection to Illustrate How Protein Evolution Is Not Random.

    Science.gov (United States)

    Paz-Y-Miño C, Guillermo; Espinosa, Avelina; Bai, Chunyan Y

    2011-09-01

    Protein evolution is not a random process. Views which attribute randomness to molecular change, deleterious nature to single-gene mutations, insufficient geological time, or population size for molecular improvements to occur, or invoke "design creationism" to account for complexity in molecular structures and biological processes, are unfounded. Scientific evidence suggests that natural selection tinkers with molecular improvements by retaining adaptive peptide sequence. We used slot-machine probabilities and ion channels to show biological directionality on molecular change. Because ion channels reside in the lipid bilayer of cell membranes, their residue location must be in balance with the membrane's hydrophobic/philic nature; a selective "pore" for ion passage is located within the hydrophobic region. We contrasted the random generation of DNA sequence for KcsA, a bacterial two-transmembrane-domain (2TM) potassium channel, from Streptomyces lividans, with an under-selection scenario, the "jackprot," which predicted much faster evolution than by chance. We wrote a computer program in JAVA APPLET version 1.0 and designed an online interface, The Jackprot Simulation http://faculty.rwu.edu/cbai/JackprotSimulation.htm, to model a numerical interaction between mutation rate and natural selection during a scenario of polypeptide evolution. Winning the "jackprot," or highest-fitness complete-peptide sequence, required cumulative smaller "wins" (rewarded by selection) at the first, second, and third positions in each of the 161 KcsA codons ("jackdons" that led to "jackacids" that led to the "jackprot"). The "jackprot" is a didactic tool to demonstrate how mutation rate coupled with natural selection suffices to explain the evolution of specialized proteins, such as the complex six-transmembrane (6TM) domain potassium, sodium, or calcium channels. Ancestral DNA sequences coding for 2TM-like proteins underwent nucleotide "edition" and gene duplications to generate the 6

  10. Selectively Sensitizing Malignant Cells to Photothermal Therapy Using a CD44-Targeting Heat Shock Protein 72 Depletion Nanosystem.

    Science.gov (United States)

    Wang, Shouju; Tian, Ying; Tian, Wei; Sun, Jing; Zhao, Shuang; Liu, Ying; Wang, Chunyan; Tang, Yuxia; Ma, Xingqun; Teng, Zhaogang; Lu, Guangming

    2016-09-27

    Selectively enhance the therapeutic efficacy to malignancy is one of the most important issues for photothermal therapy (PTT). However, most solid tumors, such as triple negative breast cancer (TNBC), do not have identifiable surface markers to distinguish themselves from normal cells, thus it is challenging to selectively identify and eliminate those malignances by PTT. In this report, we hypothesized that, by targeting CD44 (one TNBC-overexpressed surface molecule) and depleting heat shock protein 72 (HSP72, one malignancy-specific-overexpressed thermotolerance-related chaperone) subsequently, the TNBC could be selectively sensitized to PTT and improve the accuracy of treatment. To this end, a rationally designed nanosystem gold nanostar (GNS)/siRNA against HSP72 (siHSP72)/hyaluronic acid (HA) was successfully constructed using a layer-by-layer method. Hydrodynamic diameter and zeta potential analysis demonstrated the formation of GNS/siHSP72/HA having a particle size of 73.2 ± 3.8 nm and a negative surface charge of -18.3 ± 1.6 mV. The CD44-targeting ability of GNS/siHSP72/HA was confirmed by the flow cytometer, confocal microscopic imaging, and competitive binding analysis. The HSP72 silencing efficacy of GNS/siHSP72/HA was ∼95% in complete culture medium. By targeting CD44 and depleting HSP72 sequentially, GNS/siHSP72/HA could selectively sensitize TNBC cells to hyperthermia and enhance the therapeutic efficacy to TNBC with minimal side effect both in vitro and in vivo. Other advantages of GNS/siHSP72/HA included easy synthesis, robust siRNA loading capacity, endosome/lysosome escaping ability, high photothermal conversion efficacy and superior hemo- and biocompatibility.

  11. Proteasome activator complex PA28 identified as an accessible target in prostate cancer by in vivo selection of human antibodies

    Science.gov (United States)

    Sánchez-Martín, David; Martínez-Torrecuadrada, Jorge; Teesalu, Tambet; Sugahara, Kazuki N.; Alvarez-Cienfuegos, Ana; Ximénez-Embún, Pilar; Fernández-Periáñez, Rodrigo; Martín, M. Teresa; Molina-Privado, Irene; Ruppen-Cañás, Isabel; Blanco-Toribio, Ana; Cañamero, Marta; Cuesta, Ángel M.; Compte, Marta; Kremer, Leonor; Bellas, Carmen; Alonso-Camino, Vanesa; Guijarro-Muñoz, Irene; Sanz, Laura; Ruoslahti, Erkki; Alvarez-Vallina, Luis

    2013-01-01

    Antibody cancer therapies rely on systemically accessible targets and suitable antibodies that exert a functional activity or deliver a payload to the tumor site. Here, we present proof-of-principle of in vivo selection of human antibodies in tumor-bearing mice that identified a tumor-specific antibody able to deliver a payload and unveils the target antigen. By using an ex vivo enrichment process against freshly disaggregated tumors to purge the repertoire, in combination with in vivo biopanning at optimized phage circulation time, we have identified a human domain antibody capable of mediating selective localization of phage to human prostate cancer xenografts. Affinity chromatography followed by mass spectrometry analysis showed that the antibody recognizes the proteasome activator complex PA28. The specificity of soluble antibody was confirmed by demonstrating its binding to the active human PA28αβ complex. Whereas systemically administered control phage was confined in the lumen of blood vessels of both normal tissues and tumors, the selected phage spread from tumor vessels into the perivascular tumor parenchyma. In these areas, the selected phage partially colocalized with PA28 complex. Furthermore, we found that the expression of the α subunit of PA28 [proteasome activator complex subunit 1 (PSME1)] is elevated in primary and metastatic human prostate cancer and used anti-PSME1 antibodies to show that PSME1 is an accessible marker in mouse xenograft tumors. These results support the use of PA28 as a tumor marker and a potential target for therapeutic intervention in prostate cancer. PMID:23918357

  12. Pseudo cluster randomization: a treatment allocation method to minimize contamination and selection bias.

    NARCIS (Netherlands)

    Borm, G.F.; Melis, R.J.F.; Teerenstra, S.; Peer, P.G.M.

    2005-01-01

    In some clinical trials, treatment allocation on a patient level is not feasible, and whole groups or clusters of patients are allocated to the same treatment. If, for example, a clinical trial is investigating the efficacy of various patient coaching methods and randomization is done on a patient

  13. Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels.

    Science.gov (United States)

    Grigoriadis, Dimitri E; Hoare, Samuel R J; Lechner, Sandra M; Slee, Deborah H; Williams, John A

    2009-01-01

    Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.

  14. How useful are the stages of change for targeting interventions? Randomized test of a brief intervention to reduce smoking.

    Science.gov (United States)

    Armitage, Christopher J; Arden, Madelynne A

    2008-11-01

    To see whether the stages of change are useful for targeting a brief intervention to reduce smoking based on implementation intentions. A second objective was to rule out demand characteristics as an alternative explanation for the findings of intervention studies based on the transtheoretical model and implementation intentions. Participants (N = 350) were randomized to a passive control condition (questionnaire only), active control condition (questionnaire plus instruction to plan to quit), or experimental condition (questionnaire, plan to quit, form an implementation intention). Their behavior and psychosocial orientation to quit were measured at baseline and at 2-month follow-up. Theory of planned behavior variables, nicotine dependence, and quitting. Significantly more people quit smoking in the experimental condition than in the control conditions, and the planning instructions changed intention to quit and perceived control over quitting, but not behavior. Stage of change moderated these effects such that implementation intentions worked best for individuals who were in the preparation stage at baseline. Harnessing both motivational and volitional processes seems to enhance the effectiveness of smoking cessation programs, although further work is required to clarify inconsistencies in the literature using the stages of change.

  15. Short message service (SMS)-based intervention targeting alcohol consumption among university students: study protocol of a randomized controlled trial.

    Science.gov (United States)

    Thomas, Kristin; Bendtsen, Marcus; Linderoth, Catharina; Karlsson, Nadine; Bendtsen, Preben; Müssener, Ulrika

    2017-04-04

    Despite significant health risks, heavy drinking of alcohol among university students is a widespread problem; excessive drinking is part of the social norm. A growing number of studies indicate that short message service (SMS)-based interventions are cost-effective, accessible, require limited effort by users, and can enable continuous, real-time, brief support in real-world settings. Although there is emerging evidence for the effect of SMS-based interventions in reducing alcohol consumption, more research is needed. This study aims to test the effectiveness of a newly developed SMS-based intervention targeting excessive alcohol consumption among university and college students in Sweden. The study is a two-arm randomized controlled trial with an intervention (SMS programme) and a control (treatment as usual) group. Outcome measures will be investigated at baseline and at 3-month follow up. The primary outcome is total weekly alcohol consumption. Secondary outcomes are frequency of heavy episodic drinking, highest estimated blood alcohol concentration and number of negative consequences due to excessive drinking. This study contributes knowledge on the effect of automatized SMS support to reduce excessive drinking among students compared with existing support such as Student Health Centres. ISRCTN.com, ISRCTN95054707 . Registered on 31 August 2016.

  16. Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.

    Science.gov (United States)

    Coni, Sonia; Mancuso, Anna Barbara; Di Magno, Laura; Sdruscia, Giulia; Manni, Simona; Serrao, Silvia Maria; Rotili, Dante; Spiombi, Eleonora; Bufalieri, Francesca; Petroni, Marialaura; Kusio-Kobialka, Monika; De Smaele, Enrico; Ferretti, Elisabetta; Capalbo, Carlo; Mai, Antonello; Niewiadomski, Pawel; Screpanti, Isabella; Di Marcotullio, Lucia; Canettieri, Gianluca

    2017-03-09

    SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB.

  17. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells.

    Science.gov (United States)

    Piccione, Emily C; Juarez, Silvia; Liu, Jie; Tseng, Serena; Ryan, Christine E; Narayanan, Cyndhavi; Wang, Lijuan; Weiskopf, Kipp; Majeti, Ravindra

    2015-01-01

    Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.

  18. Highly sensitive and selective analysis of widely targeted metabolomics using gas chromatography/triple-quadrupole mass spectrometry.

    Science.gov (United States)

    Tsugawa, Hiroshi; Tsujimoto, Yuki; Sugitate, Kuniyo; Sakui, Norihiro; Nishiumi, Shin; Bamba, Takeshi; Fukusaki, Eiichiro

    2014-01-01

    In metabolomics studies, gas chromatography coupled with time-of-flight or quadrupole mass spectrometry has frequently been used for the non-targeted analysis of hydrophilic metabolites. However, because the analytical platform employs the deconvolution method to extract single-metabolite information from co-eluted peaks and background noise, the extracted peak is artificial product depending on the mathematical parameters and is not completely compatible with the pure component obtained by analyzing a standard compound. Moreover, it has insufficient ability for quantitative metabolomics. Therefore, highly sensitive and selective methods capable of pure peak extraction without any complicated mathematical techniques are needed. For this purpose, we have developed a novel analytical method using gas chromatography coupled with triple-quadrupole mass spectrometry (GC-QqQ/MS). We developed a selected reaction monitoring (SRM) method to analyze the trimethylsilyl derivatives of 110 metabolites, using electron ionization. This methodology enables us to utilize two complementary techniques-non-targeted and widely targeted metabolomics in the same sample preparation protocol, which would facilitate the formulation or verification of novel hypotheses in biological sciences. The GC-QqQ/MS analysis can accurately identify a metabolite using multichannel SRM transitions and intensity ratios in the analysis of living organisms. In addition, our methodology offers a wide dynamic range, high sensitivity, and highly reproducible metabolite profiles, which will contribute to the biomarker discoveries and quality evaluations in biology, medicine, and food sciences. Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  19. Mature Epitope Density - A strategy for target selection based on immunoinformatics and exported prokaryotic proteins

    DEFF Research Database (Denmark)

    Santos, Anderson R; Pereira, Vanessa Bastos; Barbosa, Eudes

    2013-01-01

    organisms. We evaluated our computational approach by using the Mycobacterium tuberculosis (Mtb) H37Rv exoproteome as a gold standard model. A literature search was carried out on 60 out of 553 Mtb's predicted exoproteins, looking for previous experimental evidence concerning their possible antigenicity...... proteins were confirmed as related. There was no experimental evidence of antigenic or pathogenic contributions for three of the highest MED-scored Mtb proteins. Hence, these three proteins could represent novel putative vaccine and drug targets for Mtb. A web version of MED is publicly available online...

  20. Evaluation of Immunomodulatory Effect: Selection of the Correct Targets for Immunostimulation Study

    OpenAIRE

    Yeap, Swee K.; Mashitoh B.A. Rahman; Alitheen, Noorjahan B.; Wan Y. Ho; Omar, Abdul R; Boon K. Beh; Huynh Ky

    2011-01-01

    Problem statement: Numerous plants or remedies that are traditionally used for various diseases had been claimed to maintain general good health, particularly the immune system. With the advanced understanding on immunology and ethnopharmacology, study on the interaction of this herb with the immune system is critical to understand the safety and its efficacy as a potent immunomodulatory agent. Approach: Selecting proper immune cells from a suitable immune organ allowed for the understanding ...

  1. Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials.

    Science.gov (United States)

    Kim, Seung Tae; Kim, Kyoung-Mee; Kim, Nayoung K D; Park, Joon Oh; Ahn, Soomin; Yun, Jae-Won; Kim, Kyu-Tae; Park, Se Hoon; Park, Peter J; Kim, Hee Cheol; Sohn, Tae Sung; Choi, Dong Il; Cho, Jong Ho; Heo, Jin Seok; Kwon, Wooil; Lee, Hyuk; Min, Byung-Hoon; Hong, Sung No; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Park, Woong-Yang; Lee, Jeeyun

    2017-10-01

    Molecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular-screening program was intended to route participants to different candidate drugs in trials based on clinical-sequencing reports. In this screening program, we used a custom target-enrichment panel consisting of cancer-related genes to interrogate single-nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381-gene cancer-panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker-selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. This study demonstrated that the panel-based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker-selected clinical trials. Given the expanding list of biomarker-selected trials, the guidance percentage to matched trials is anticipated to increase. © AlphaMed Press 2017.

  2. Improvement of a puromycin-linker to extend the selection target varieties in cDNA display method.

    Science.gov (United States)

    Ueno, Shingo; Kimura, Shinnosuke; Ichiki, Takanori; Nemoto, Naoto

    2012-12-31

    cDNA display using a puromycin-linker to covalently bridge a protein and its coding cDNA is a stable and efficient in vitro protein selection method. The optimal design of the often-used puromycin-linker is vital for effective selection. In this report, an improved puromycin-linker containing deoxyinosine bases as cleavage sites, which are recognized by endonuclease V, was introduced to extend the variety of the selection targets to molecules such as RNA. The introduction of this linker enables efficient in vitro protein selection without contamination from RNase T1, which is used for the conventional linker containing ribonucleotide G bases. In addition, mRNA-protein fusion efficiency was found to not depend on the length of the flexible poly (ethylene glycol) (PEG) region of the linker. These findings will allow practical and easy-to-use in vitro protein selection by cDNA display. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Application of Ultrasound to Selectively Localize Nanodroplets for Targeted Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Paul A. Dayton

    2006-07-01

    Full Text Available Lipid-coated perfluorocarbon nanodroplets are submicrometer-diameter liquid-filled droplets with proposed applications in molecularly targeted therapeutics and ultrasound (US imaging. Ultrasonic molecular imaging is unique in that the optimal application of these agents depends not only on the surface chemistry, but also on the applied US field, which can increase receptor-ligand binding and membrane fusion. Theory and experiments are combined to demonstrate the displacement of perfluorocarbon nanoparticles in the direction of US propagation, where a traveling US wave with a peak pressure on the order of megapascals and frequency in the megahertz range produces a particle translational velocity that is proportional to acoustic intensity and increases with increasing center frequency. Within a vessel with a diameter on the order of hundreds of micrometers or larger, particle velocity on the order of hundreds of micrometers per second is produced and the dominant mechanism for droplet displacement is shown to be bulk fluid streaming. A model for radiation force displacement of particles is developed and demonstrates that effective particle displacement should be feasible in the microvasculature. In a flowing system, acoustic manipulation of targeted droplets increases droplet retention. Additionally, we demonstrate the feasibility of US-enhanced particle internalization and therapeutic delivery.

  4. Targeting lipodisks enable selective delivery of anticancer peptides to tumor cells.

    Science.gov (United States)

    Ahlgren, Sara; Reijmar, Karin; Edwards, Katarina

    2017-10-01

    Issues concerning non-specificity, degradation and hemolysis severely hamper the development of membranolytic amphiphilic peptides into safe and efficient anticancer agents. To increase the therapeutic potential, we have previously developed a strategy based on formulation of the peptides in biocompatible nanosized lipodisks. Studies using melittin as model peptide show that the proteolytic degradation and hemolytic effect of the peptide are substantially reduced upon loading in lipodisks. Here, we explored the possibilities to increase the specificity and boost the cytotoxicity of melittin to tumor cells by use of targeting lipodisk. We demonstrate that small (~20 nm) EGF-targeted lipodisks can be produced and loaded with substantial amounts of peptide (lipid/peptide molar ratio >7) by means of a simple and straightforward preparation protocol. In vitro cell studies confirm specific binding of the peptide-loaded disks to tumor cells and suggest that cellular internalization of the disks results in a significantly improved cell-killing effect. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Presence of psychoactive substances in oral fluid from randomly selected drivers in Denmark

    DEFF Research Database (Denmark)

    Simonsen, K. Wiese; Steentoft, A.; Hels, Tove

    2012-01-01

    This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Oral fluid samples (n = 3002) were collected randomly from drivers using a sampling scheme stratified by time, season...... of narcotic drugs. It can be concluded that driving under the influence of drugs is as serious a road safety problem as drunk driving.......This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Oral fluid samples (n = 3002) were collected randomly from drivers using a sampling scheme stratified by time, season...

  6. Presence of psychoactive substances in oral fluid from randomly selected drivers in Denmark

    DEFF Research Database (Denmark)

    Simonsen, Kirsten Wiese; Steentoft, Anni; Hels, Tove

    2012-01-01

    This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Oral fluid samples (n = 3002) were collected randomly from drivers using a sampling scheme stratified by time, season....... It can be concluded that driving under the influence of drugs is as serious a road safety problem as drunk driving.......This roadside study is the Danish part of the EU-project DRUID (Driving under the Influence of Drugs, Alcohol, and Medicines) and included three representative regions in Denmark. Oral fluid samples (n = 3002) were collected randomly from drivers using a sampling scheme stratified by time, season...

  7. Feature selection and classification of mechanical fault of an induction motor using random forest classifier

    Directory of Open Access Journals (Sweden)

    Raj Kumar Patel

    2016-09-01

    Full Text Available Fault detection and diagnosis is the most important technology in condition-based maintenance (CBM system for rotating machinery. This paper experimentally explores the development of a random forest (RF classifier, a recently emerged machine learning technique, for multi-class mechanical fault diagnosis in bearing of an induction motor. Firstly, the vibration signals are collected from the bearing using accelerometer sensor. Parameters from the vibration signal are extracted in the form of statistical features and used as input feature for the classification problem. These features are classified through RF classifiers for four class problems. The prime objective of this paper is to evaluate effectiveness of random forest classifier on bearing fault diagnosis. The obtained results compared with the existing artificial intelligence techniques, neural network. The analysis of results shows the better performance and higher accuracy than the well existing techniques.

  8. PLS-based and regularization-based methods for the selection of relevant variables in non-targeted metabolomics data

    Directory of Open Access Journals (Sweden)

    Renata Bujak

    2016-07-01

    Full Text Available Non-targeted metabolomics constitutes a part of systems biology and aims to determine many metabolites in complex biological samples. Datasets obtained in non-targeted metabolomics studies are multivariate and high-dimensional due to the sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA without and with multiple testing correction as well as least absolute shrinkage and selection operator (LASSO were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction, selected 46 and 218 variables based on VIP criteria using Pareto and UV scaling, respectively. In the case of the PH study, 217 and 320 variables were selected based on VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built with multiple testing correction, selected 4 and 19 variables as statistically significant in terms of Pareto and UV scaling, respectively. For PH study, 14 and 18 variables were selected based on VIP criteria in terms of Pareto and UV scaling, respectively. Additionally, the concept and fundaments of the least absolute shrinkage and selection operator (LASSO with bootstrap procedure evaluating reproducibility of results, was demonstrated. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3% and 100%. However, apart from the popularity of PLS-DA and OPLS-DA methods in metabolomics, it should be highlighted that they do not control type I or type II error, but only arbitrarily establish a cut-off value for PLS-DA loadings

  9. Animal models for medications development targeting alcohol abuse using selectively bred rat lines: Neurobiological and pharmacological validity

    Science.gov (United States)

    Bell, Richard L.; Sable, Helen J.K.; Colombo, Giancarlo; Hyytia, Petri; Rodd, Zachary A.; Lumeng, Lawrence

    2012-01-01

    The purpose of this review paper is to present evidence that rat animal models of alcoholism provide an ideal platform for developing and screening medications that target alcohol abuse and dependence. The focus is on the 5 oldest international rat lines that have been selectively bred for a high alcohol-consumption phenotype. The behavioral and neurochemical phenotypes of these rat lines are reviewed and placed in the context of the clinical literature. The paper presents behavioral models for assessing the efficacy of pharmaceuticals for the treatment of alcohol abuse and dependence in rodents, with particular emphasis on rats. Drugs that have been tested for their effectiveness in reducing alcohol/ethanol consumption and/or self-administration by these rat lines and their putative site of action are summarized. The paper also presents some current and future directions for developing pharmacological treatments targeting alcohol abuse and dependence. PMID:22841890

  10. Effectiveness of shared goal setting and decision making to achieve treatment targets in type 2 diabetes patients : A cluster-randomized trial (OPTIMAL)

    NARCIS (Netherlands)

    Den Ouden, Henk; Vos, Rimke C.; Rutten, Guy E.H.M.|info:eu-repo/dai/nl/074622781

    2017-01-01

    Objective: About 20% of patients with type 2 diabetes achieve all their treatment targets. Shared decision making (SDM) using a support aid based on the 5-years results of the ADDITION study on multifactorial treatment, could increase this proportion. Research design and methods: Cluster-randomized

  11. Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design

    NARCIS (Netherlands)

    Nielsen, Niklas; Wetterslev, Jørn; al-Subaie, Nawaf; Andersson, Bertil; Bro-Jeppesen, John; Bishop, Gillian; Brunetti, Iole; Cranshaw, Julius; Cronberg, Tobias; Edqvist, Kristin; Erlinge, David; Gasche, Yvan; Glover, Guy; Hassager, Christian; Horn, Janneke; Hovdenes, Jan; Johnsson, Jesper; Kjaergaard, Jesper; Kuiper, Michael; Langørgen, Jørund; Macken, Lewis; Martinell, Louise; Martner, Patrik; Pellis, Thomas; Pelosi, Paolo; Petersen, Per; Persson, Stefan; Rundgren, Malin; Saxena, Manoj; Svensson, Robert; Stammet, Pascal; Thorén, Anders; Undén, Johan; Walden, Andrew; Wallskog, Jesper; Wanscher, Michael; Wise, Matthew P.; Wyon, Nicholas; Aneman, Anders; Friberg, Hans

    2012-01-01

    Background Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32 degrees C to 34 degrees C for 12 to 24

  12. Extending data worth methods to select multiple observations targeting specific hydrological predictions of interest

    Science.gov (United States)

    Vilhelmsen, Troels N.; Ferré, Ty P. A.

    2016-04-01

    Hydrological models are often developed to forecasting future behavior in response due to natural or human induced changes in stresses affecting hydrologic systems. Commonly, these models are conceptualized and calibrated based on existing data/information about the hydrological conditions. However, most hydrologic systems lack sufficient data to constrain models with adequate certainty to support robust decision making. Therefore, a key element of a hydrologic study is the selection of additional data to improve model performance. Given the nature of hydrologic investigations, it is not practical to select data sequentially, i.e. to choose the next observation, collect it, refine the model, and then repeat the process. Rather, for timing and financial reasons, measurement campaigns include multiple wells or sampling points. There is a growing body of literature aimed at defining the expected data worth based on existing models. However, these are almost all limited to identifying single additional observations. In this study, we present a methodology for simultaneously selecting multiple potential new observations based on their expected ability to reduce the uncertainty of the forecasts of interest. This methodology is based on linear estimates of the predictive uncertainty, and it can be used to determine the optimal combinations of measurements (location and number) established to reduce the uncertainty of multiple predictions. The outcome of the analysis is an estimate of the optimal sampling locations; the optimal number of samples; as well as a probability map showing the locations within the investigated area that are most likely to provide useful information about the forecasting of interest.

  13. Oligonucleotide Sensor Based on Selective Capture of Upconversion Nanoparticles Triggered by Target-Induced DNA Interstrand Ligand Reaction.

    Science.gov (United States)

    Mendez-Gonzalez, Diego; Laurenti, Marco; Latorre, Alfonso; Somoza, Alvaro; Vazquez, Ana; Negredo, Ana Isabel; López-Cabarcos, Enrique; Calderón, Oscar G; Melle, Sonia; Rubio-Retama, Jorge

    2017-04-12

    We present a sensor that exploits the phenomenon of upconversion luminescence to detect the presence of specific sequences of small oligonucleotides such as miRNAs among others. The sensor is based on NaYF4:Yb,Er@SiO2 nanoparticles functionalized with ssDNA that contain azide groups on the 3' ends. In the presence of a target sequence, interstrand ligation is possible via the click-reaction between one azide of the upconversion probe and a DBCO-ssDNA-biotin probe present in the solution. As a result of this specific and selective process, biotin is covalently attached to the surface of the upconversion nanoparticles. The presence of biotin on the surface of the nanoparticles allows their selective capture on a streptavidin-coated support, giving a luminescent signal proportional to the amount of target strands present in the test samples. With the aim of studying the analytical properties of the sensor, total RNA samples were extracted from healthy mosquitoes and were spiked-in with a specific target sequence at different concentrations. The result of these experiments revealed that the sensor was able to detect 10-17 moles per well (100 fM) of the target sequence in mixtures containing 100 ng of total RNA per well. A similar limit of detection was found for spiked human serum samples, demonstrating the suitability of the sensor for detecting specific sequences of small oligonucleotides under real conditions. In contrast, in the presence of noncomplementary sequences or sequences having mismatches, the luminescent signal was negligible or conspicuously reduced.

  14. Selective nerve root blocks vs. caudal epidural injection for single level prolapsed lumbar intervertebral disc - A prospective randomized study.

    Science.gov (United States)

    Singh, Sudhir; Kumar, Sanjiv; Chahal, Gaurav; Verma, Reetu

    2017-01-01

    Chronic lumbar radiculopathy has a lifetime prevalence of 5.3% in men and 3.7% in women. It usually resolves spontaneously, but up to 30% cases will have pronounced symptoms even after one year. A prospective randomized single-blind study was conducted to compare the efficacy of caudal epidural steroid injection and selective nerve root block in management of pain and disability in cases of lumbar disc herniation. Eighty patients with confirmed single-level lumbar disc herniation were equally divided in two groups: (a) caudal epidural and (b) selective nerve root block group, by a computer-generated random allocation method. The caudal group received three injections of steroid mixed with local anesthetics while selective nerve root block group received single injection of steroid mixed with local anesthetic agent. Patients were assessed for pain relief and reduction in disability. In SNRB group, pain reduced by more than 50% up till 6 months, while in caudal group more than 50% reduction of pain was maintained till 1 year. The reduction in ODI in SNRB group was 52.8% till 3 months, 48.6% till 6 months, and 46.7% at 1 year, while in caudal group the improvement was 59.6%, 64.6%, 65.1%, and 65.4% at corresponding follow-up periods, respectively. Caudal epidural block is an easy and safe method with better pain relief and improvement in functional disability than selective nerve root block. Selective nerve root block injection is technically more demanding and has to be given by a skilled anesthetist.

  15. Targeting ferritin receptors for the selective delivery of imaging and therapeutic agents to breast cancer cells

    Science.gov (United States)

    Geninatti Crich, S.; Cadenazzi, M.; Lanzardo, S.; Conti, L.; Ruiu, R.; Alberti, D.; Cavallo, F.; Cutrin, J. C.; Aime, S.

    2015-04-01

    In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation.In this work the selective uptake of native horse spleen ferritin and apoferritin loaded with MRI contrast agents has been assessed in human breast cancer cells (MCF-7 and MDA-MB-231). The higher expression of L-ferritin receptors (SCARA5) led to an enhanced uptake in MCF-7 as shown in T2 and T1 weighted MR images, respectively. The high efficiency of ferritin internalization in MCF-7 has been exploited for the simultaneous delivery of curcumin, a natural therapeutic molecule endowed with antineoplastic and anti-inflammatory action, and the MRI contrast agent Gd-HPDO3A. This theranostic system is able to treat selectively breast cancer cells over-expressing ferritin receptors. By entrapping in apoferritin both Gd-HPDO3A and curcumin, it was possible to deliver a therapeutic dose of 167 μg ml-1 (as calculated by MRI) of this natural drug to MCF-7 cells, thus obtaining a significant reduction of cell proliferation. Electronic supplementary information (ESI) available: Competition studies with free apoferritin, Fig. S1; APO-FITC intracellular distribution by

  16. Site selection and directional models of deserts used for ERBE validation targets

    Science.gov (United States)

    Staylor, W. F.

    1986-01-01

    Broadband shortwave and longwave radiance measurements obtained from the Nimbus 7 Earth Radiation Budget scanner were used to develop reflectance and emittance models for the Sahara, Gibson, and Saudi Deserts. These deserts will serve as in-flight validation targets for the Earth Radiation Budget Experiment being flown on the Earth Radiation Budget Satellite and two National Oceanic and Atmospheric Administration polar satellites. The directional reflectance model derived for the deserts was a function of the sum and product of the cosines of the solar and viewing zenith angles, and thus reciprocity existed between these zenith angles. The emittance model was related by a power law of the cosine of the viewing zenith angle.

  17. Evaluation of targeted selective treatments in sheep in Italy: effects on faecal worm egg count and milk production in four case studies.

    Science.gov (United States)

    Cringoli, G; Rinaldi, L; Veneziano, V; Mezzino, L; Vercruysse, J; Jackson, F

    2009-09-16

    The aim of the present paper was to assess the benefit of targeted selective treatments (TSTs) on milk production and faecal worm egg count, in four commercial dairy sheep farms in southern Italy where animals were exposed to natural infection with gastrointestinal (GI) strongyles. On each farm, three similar groups of 20 animals each were formed and randomly assigned to the following treatments: strategic prophylactic treatment (SPT) group, targeted selective treatment group, and control (C) group. The TST schemes used were different between farms with regard to the indicators for treatment (FAMACHA or faecal egg count (FEC) or milk production) and the timing of treatment (periparturient or postparturient). Regarding milk production, on the four study farms the mean daily milk production in the SPT ewes was higher than those of the controls on Farms 1, 2, 3 and 4 by 13.6%, 30.4%, 37.0% and 5.5%, respectively. In the case of Farms 2 and 3 these differences were significant (PFAMACHA-based TST (Farms 1 and 2) had no positive effects on GI strongyle egg counts. In the FEC-based TST group on Farm 3 both the TST and SPT treatments reduced FEC. In the milk production-based TST group (Farm 4), no conclusion could be drawn regarding strategic efficacy since there was also a decrease in GI strongyle FEC in the control group. The findings of the present study demonstrate that TST can be considered as a potentially useful anthelmintic strategy in southern Italy, but the timing of treatments seems to be more crucial for the strategic and production efficacy than the indicators used for those treatments. From a practical point of view using milk production as a TST indicator appeared to be the most user-friendly approach for farmers; however, further studies will be needed to confirm its validity and acceptability.

  18. 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation.

    Science.gov (United States)

    Wang, Juan; Peng, Liang; Zhang, Ruihua; Zheng, Zihan; Chen, Chun; Cheung, Ka Lung; Cui, Miao; Bian, Guanglin; Xu, Feihong; Chiang, David; Hu, Yuan; Chen, Ye; Lu, Geming; Yang, Jianjun; Zhang, Hui; Yang, Jianfei; Zhu, Hongfa; Chen, Shu-Hsia; Liu, Kebin; Zhou, Ming-Ming; Sikora, Andrew G; Li, Liwu; Jiang, Bo; Xiong, Huabao

    2016-04-12

    While it is well established that treatment of cancer patients with 5-Fluorouracil (5-FU) can result in immune suppression, the exact function of 5-FU in the modulation of immune cells has not been fully established. We found that low dose 5-FU selectively suppresses TH17 and TH1 cell differentiation without apparent effect on Treg, TH2, and significantly suppresses thymidylate synthase (TS) expression in TH17 and TH1 cells but has a lesser effect in tumor cells and macrophages. Interestingly, the basal expression of TS varies significantly between T helper phenotypes and knockdown of TS significantly impairs TH17 and TH1 cell differentiation without affecting the differentiation of either Treg or TH2 cells. Finally, low dose 5-FU is effective in ameliorating colitis development by suppressing TH17 and TH1 cell development in a T cell transfer colitis model. Taken together, the results highlight the importance of the anti-inflammatory functions of low dose 5-FU by selectively suppressing TH17 and TH1 immune responses.

  19. DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial

    Science.gov (United States)

    2014-01-01

    Background Vitamin D levels are alarmingly low (respiratory tract infections (URTI), asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations, two of the most common and costly illnesses of early childhood. The objectives of this study are: 1) to compare the effect of ‘high dose’ (2000 IU/day) vs. ‘standard dose’ (400 IU/day) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children; and 2) to assess the effect of ‘high dose’ vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI. Methods/Design This study is a pragmatic randomized controlled trial. Over 4 successive winters we will recruit 750 healthy children 1–5 years of age. Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be randomized to the ‘standard dose’ or ‘high dose’ oral supplemental vitamin D for a minimum of 4 months (200 children per group). Parents will obtain a nasal swab from their child with each URTI, report the number of asthma exacerbations and complete symptom checklists. Unscheduled physician visits for URTIs and asthma exacerbations will be recorded. By May, a blood sample will be drawn to determine vitamin D serum levels. The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model. Secondary analyses will compare vitamin D serum levels, asthma exacerbations and the frequency of specific viral agents between groups. Discussion Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs

  20. Stepped care targeting psychological distress in head and neck and lung cancer patients: a randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Krebber Anne-Marie H

    2012-05-01

    Full Text Available Abstract Background Psychological distress is common in cancer survivors. Although there is some evidence on effectiveness of psychosocial care in distressed cancer patients, referral rate is low. Lack of adequate screening instruments in oncology settings and insufficient availability of traditional models of psychosocial care are the main barriers. A stepped care approach has the potential to improve the efficiency of psychosocial care. The aim of the study described herein is to evaluate efficacy of a stepped care strategy targeting psychological distress in cancer survivors. Methods/design The study is designed as a randomized clinical trial with 2 treatment arms: a stepped care intervention programme versus care as usual. Patients treated for head and neck cancer (HNC or lung cancer (LC are screened for distress using OncoQuest, a computerized touchscreen system. After stratification for tumour (HNC vs. LC and stage (stage I/II vs. III/IV, 176 distressed patients are randomly assigned to the intervention or control group. Patients in the intervention group will follow a stepped care model with 4 evidence based steps: 1. Watchful waiting, 2. Guided self-help via Internet or a booklet, 3. Problem Solving Treatment administered by a specialized nurse, and 4. Specialized psychological intervention or antidepressant medication. In the control group, patients receive care as usual which most often is a single interview or referral to specialized intervention. Primary outcome is the Hospital Anxiety and Depression Scale (HADS. Secondary outcome measures are a clinical level of depression or anxiety (CIDI, quality of life (EQ-5D, EORTC QLQ-C30, QLQ-HN35, QLQ-LC13, patient satisfaction with care (EORTC QLQ-PATSAT, and costs (health care utilization and work loss (TIC-P and PRODISQ modules. Outcomes are evaluated before and after intervention and at 3, 6, 9 and 12 months after intervention. Discussion Stepped care is a system of delivering and

  1. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles.

    Science.gov (United States)

    Li, Wuping; Asokan, Aravind; Wu, Zhijian; Van Dyke, Terry; DiPrimio, Nina; Johnson, Jarrod S; Govindaswamy, Lakshmanan; Agbandje-McKenna, Mavis; Leichtle, Stefan; Redmond, D Eugene; McCown, Thomas J; Petermann, Kimberly B; Sharpless, Norman E; Samulski, Richard J

    2008-07-01

    We report a DNA shuffling-based approach for developing cell type-specific vectors through directed evolution. Capsid genomes of adeno-associated virus (AAV) serotypes 1-9 were randomly fragmented and reassembled using PCR to generate a chimeric capsid library. A single infectious clone (chimeric-1829) containing genome fragments from AAV1, 2, 8, and 9 was isolated from an integrin minus hamster melanoma cell line previously shown to have low permissiveness to AAV. Molecular modeling studies suggest that AAV2 contributes to surface loops at the icosahedral threefold axis of symmetry, while AAV1 and 9 contribute to two- and fivefold symmetry interactions, respectively. The C-terminal domain (AAV9) was identified as a critical structural determinant of melanoma tropism through rational mutagenesis. Chimeric-1829 utilizes heparan sulfate as a primary receptor and transduces melanoma cells more efficiently than all serotypes. Further, chimeric-1829 demonstrates altered tropism in rodent skeletal muscle, liver, and brain including nonhuman primates. We determined a unique immunological profile based on neutralizing antibody (NAb) titer and crossreactivity studies strongly supporting isolation of a synthetic laboratory-derived capsid variant. Application of this technology to alternative cell/tissue types using AAV or other viral capsid sequences is likely to yield a new class of biological nanoparticles as vectors for human gene transfer.

  2. Engineering and Selection of Shuffled AAV Genomes: A New Strategy for Producing Targeted Biological Nanoparticles.

    Science.gov (United States)

    Li, Wuping; Asokan, Aravind; Wu, Zhijian; Van Dyke, Terry; DiPrimio, Nina; Johnson, Jarrod S; Govindaswamy, Lakshmanan; Agbandje-McKenna, Mavis; Leichtle, Stefan; Eugene Redmond, D; McCown, Thomas J; Petermann, Kimberly B; Sharpless, Norman E; Samulski, Richard J

    2008-07-01

    We report a DNA shuffling-based approach for developing cell type-specific vectors through directed evolution. Capsid genomes of adeno-associated virus (AAV) serotypes 1-9 were randomly fragmented and reassembled using PCR to generate a chimeric capsid library. A single infectious clone (chimeric-1829) containing genome fragments from AAV1, 2, 8, and 9 was isolated from an integrin minus hamster melanoma cell line previously shown to have low permissiveness to AAV. Molecular modeling studies suggest that AAV2 contributes to surface loops at the icosahedral threefold axis of symmetry, while AAV1 and 9 contribute to two- and fivefold symmetry interactions, respectively. The C-terminal domain (AAV9) was identified as a critical structural determinant of melanoma tropism through rational mutagenesis. Chimeric-1829 utilizes heparan sulfate as a primary receptor and transduces melanoma cells more efficiently than all serotypes. Further, chimeric-1829 demonstrates altered tropism in rodent skeletal muscle, liver, and brain including nonhuman primates. We determined a unique immunological profile based on neutralizing antibody (NAb) titer and crossreactivity studies strongly supporting isolation of a synthetic laboratory-derived capsid variant. Application of this technology to alternative cell/tissue types using AAV or other viral capsid sequences is likely to yield a new class of biological nanoparticles as vectors for human gene transfer. Copyright © 2008 The American Society of Gene Therapy. Published by Elsevier Inc. All rights reserved.

  3. A Novel Method for Gene-Specific Enhancement of Protein Translation by Targeting 5'UTRs of Selected Tumor Suppressors.

    Science.gov (United States)

    Master, Adam; Wójcicka, Anna; Giżewska, Kamilla; Popławski, Piotr; Williams, Graham R; Nauman, Alicja

    2016-01-01

    Translational control is a mechanism of protein synthesis regulation emerging as an important target for new therapeutics. Naturally occurring microRNAs and synthetic small inhibitory RNAs (siRNAs) are the most recognized regulatory molecules acting via RNA interference. Surprisingly, recent studies have shown that interfering RNAs may also activate gene transcription via the newly discovered phenomenon of small RNA-induced gene activation (RNAa). Thus far, the small activating RNAs (saRNAs) have only been demonstrated as promoter-specific transcriptional activators. We demonstrate that oligonucleotide-based trans-acting factors can also specifically enhance gene expression at the level of protein translation by acting at sequence-specific targets within the messenger RNA 5'-untranslated region (5'UTR). We designed a set of short synthetic oligonucleotides (dGoligos), specifically targeting alternatively spliced 5'UTRs in transcripts expressed from the THRB and CDKN2A suppressor genes. The in vitro translation efficiency of reporter constructs containing alternative TRβ1 5'UTRs was increased by up to more than 55-fold following exposure to specific dGoligos. Moreover, we found that the most folded 5'UTR has higher translational regulatory potential when compared to the weakly folded TRβ1 variant. This suggests such a strategy may be especially applied to enhance translation from relatively inactive transcripts containing long 5'UTRs of complex structure. This report represents the first method for gene-specific translation enhancement using selective trans-acting factors designed to target specific 5'UTR cis-acting elements. This simple strategy may be developed further to complement other available methods for gene expression regulation including gene silencing. The dGoligo-mediated translation-enhancing approach has the potential to be transferred to increase the translation efficiency of any suitable target gene and may have future application in gene therapy

  4. Predicting the Interactome of Xanthomonas oryzae pathovar oryzae for target selection and DB service

    Directory of Open Access Journals (Sweden)

    Yoon Kyong-Oh

    2008-01-01

    Full Text Available Abstract Background Protein-protein interactions (PPIs play key roles in various cellular functions. In addition, some critical inter-species interactions such as host-pathogen interactions and pathogenicity occur through PPIs. Phytopathogenic bacteria infect hosts through attachment to host tissue, enzyme secretion, exopolysaccharides production, toxins release, iron acquisition, and effector proteins secretion. Many such mechanisms involve some kind of protein-protein interaction in hosts. Our first aim was to predict the whole protein interaction pairs (interactome of Xanthomonas oryzae pathovar oryzae (Xoo that is an important pathogenic bacterium that causes bacterial blight (BB in rice. We developed a detection protocol to find possibly interacting proteins in its host using whole genome PPI prediction algorithms. The second aim was to build a DB server and a bioinformatic procedure for finding target proteins in Xoo for developing pesticides that block host-pathogen protein interactions within critical biochemical pathways. Description A PPI network in Xoo proteome was predicted by bioinformatics algorithms: PSIMAP, PEIMAP, and iPfam. We present the resultant species specific interaction network and host-pathogen interaction, XooNET. It is a comprehensive predicted initial PPI data for Xoo. XooNET can be used by experimentalists to pick up protein targets for blocking pathological interactions. XooNET uses most of the major types of PPI algorithms. They are: 1 Protein Structural Interactome MAP (PSIMAP, a method using structural domain of SCOP, 2 Protein Experimental Interactome MAP (PEIMAP, a common method using public resources of experimental protein interaction information such as HPRD, BIND, DIP, MINT, IntAct, and BioGrid, and 3 Domain-domain interactions, a method using Pfam domains such as iPfam. Additionally, XooNET provides information on network properties of the Xoo interactome. Conclusion XooNET is an open and free public

  5. Signaling by 4-hydroxy-2-nonenal: Exposure protocols, target selectivity and degradation.

    Science.gov (United States)

    Zhang, Hongqiao; Forman, Henry Jay

    2017-03-01

    4-hydroxy-2-nonenal (HNE), a major non-saturated aldehyde product of lipid peroxidation, has been extensively studied as a signaling messenger. In these studies a wide range of HNE concentrations have been used, ranging from the unstressed plasma concentration to far beyond what would be found in actual pathophysiological condition. In addition, accumulating evidence suggest that signaling protein modification by HNE is specific with only those proteins with cysteine, histidine, and lysine residues located in certain sequence or environments adducted by HNE. HNE-signaling is further regulated through the turnover of HNE-signaling protein adducts through proteolytic process that involve proteasomes, lysosomes and autophagy. This review discusses the HNE concentrations and exposure modes used in signaling studies, the selectivity of the HNE-adduction site, and the turnover of signaling protein adducts. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Viral Ubiquitin Ligase Stimulates Selective Host MicroRNA Expression by Targeting ZEB Transcriptional Repressors

    Science.gov (United States)

    Kim, Ju Youn; Leader, Andrew; Stoller, Michelle L.; Coen, Donald M.; Wilson, Angus C.

    2017-01-01

    Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/δ-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors. PMID:28783105

  7. Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation.

    Science.gov (United States)

    Goode, Kourtney M; Petrov, Dino P; Vickman, Renee E; Crist, Scott A; Pascuzzi, Pete E; Ratliff, Tim L; Davisson, V Jo; Hazbun, Tony R

    2017-08-01

    Inhibition of Hsp90 is desirable due to potential downregulation of oncogenic clients. Early generation inhibitors bind to the N-terminal domain (NTD) but C-terminal domain (CTD) inhibitors are a promising class because they do not induce a heat shock response. Here we present a new structural class of CTD binding molecules with a unique allosteric inhibition mechanism. A hit molecule, NSC145366, and structurally similar probes were assessed for inhibition of Hsp90 activities. A ligand-binding model was proposed indicating a novel Hsp90 CTD binding site. Client protein downregulation was also determined. NSC145366 interacts with the Hsp90 CTD and has anti-proliferative activity in tumor cell lines (GI50=0.2-1.9μM). NSC145366 increases Hsp90 oligomerization resulting in allosteric inhibition of NTD ATPase activity (IC50=119μM) but does not compete with NTD or CTD-ATP binding. Treatment of LNCaP prostate tumor cells resulted in selective client protein downregulation including AR and BRCA1 but without a heat shock response. Analogs had similar potencies in ATPase and chaperone activity assays and variable effects on oligomerization. In silico modeling predicted a binding site at the CTD dimer interface distinct from the nucleotide-binding site. A set of symmetrical scaffold molecules with bisphenol A cores induced allosteric inhibition of Hsp90. Experimental evidence and molecular modeling suggest that the binding site is independent of the CTD-ATP site and consistent with unique induction of allosteric effects. Allosteric inhibition of Hsp90 via a mechanism used by the NSC145366-based probes is a promising avenue for selective oncogenic client downregulation. Copyright © 2017. Published by Elsevier B.V.

  8. Host selection in the forest interior: cowbirds target ground-nesting species

    Science.gov (United States)

    Hahn, D.C.; Hatfield, J.S.

    2000-01-01

    We investigated patterns of cowbird host selection in a large (1300 ha), unfragmented forest in eastern New York in 1992-3 to determine whether cowbird parasitism rates can be attributed to species-specific traits or to other features associated with nest sites. Nest height was significantly associated with parasitism (P = 0.003) in this community of 23 species (n = 430 nests, 23% parasitized). Further analysis revealed that the difference in mean nest heights between parasitized and unparasitized nests was due to species identity, and within each species there was no difference in mean nest heights between parasitized and unparasitized nests. These results imply that during 1992-3 cowbirds in this forest specialized on species that have low nests and did not necessarily select low nests regardless of species. This was further supported by a negative association across all 23 species between mean nest height and parasitism rate (P = 0.03). Thus, although most of the forest-nesting species in this community experienced cowbird parasitism, there was a tendency for higher parasitism rates on low-nesting species such as the Ovenbird, Black-and-white Warbler, Louisiana Waterthrush, Veery, and Hermit Thrush. The Wood Thrush, a mid-range nester which is heavily parasitized in southern Illinois, experienced only 10% parasitism in our site and ranked 9th in parasitism rate, although it was the most abundant species in this forest in terms of the number of nests found. A long-term study is necessary to determine whether this cowbird population consistently parasitizes the ground-nesting species of this forest community more often than those nesting at higher levels or whether they periodically shift among hosts at different heights and in different habitats across the local landscape.

  9. Group cognitive behavioral therapy targeting intolerance of uncertainty: a randomized trial for older Chinese adults with generalized anxiety disorder.

    Science.gov (United States)

    Hui, Chen; Zhihui, Yang

    2017-12-01

    China has entered the aging society, but the social support systems for the elderly are underdeveloped, which may make the elderly feel anxiety about their health and life quality. Given the prevalence of generalized anxiety disorder (GAD) in the elderly, it is very important to pay more attention to the treatment for old adults. Although cognitive behavioral therapy targeting intolerance of uncertainty (CBT-IU) has been applied to different groups of patients with GAD, few studies have been performed to date. In addition, the effects of CBT-IU are not well understood, especially when applied to older adults with GAD. Sixty-three Chinese older adults with a principal diagnosis of GAD were enrolled. Of these, 32 were randomized to receive group CBT-IU (intervention group) and 31 were untreated (control group). GAD and related symptoms were assessed using the Penn State Worry Questionnaire, Intolerance of Uncertainty Scale-Chinese Version, Beck Anxiety Inventory, Beck Depression Inventory, Why Worry-II scale, Cognitive Avoidance Questionnaire, Generalized Anxiety Disorder Questionnaire-IV, and Generalized Anxiety Disorder Severity Scale across the intervention. The changes between pre and after the intervention were collected, as well as the six-month follow-up. F test and repeated-measures ANOVA were conducted to analyze the data. Compared to control group, the measures' scores of experimental group decreased significantly after the intervention and six-month follow-up. Besides the main effects for time and group were significant, the interaction effect for group × time was also significant. These results indicated the improvement of the CBT-IU group and the persistence of effect after six months. Group CBT-IU is effective in Chinese older adults with GAD. The effects of CBT-IU on GAD symptoms persist for at least six months after treatment.

  10. In-Silico Analyses of Sesquiterpene-Related Compounds on Selected Leishmania Enzyme-Based Targets

    Directory of Open Access Journals (Sweden)

    Freddy A. Bernal

    2014-04-01

    Full Text Available A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1, N-myristoyl transferase (NMT, cysteine synthase (CS, trypanothione synthetase (TryS]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds.

  11. Selection of locations of knots for linear splines in random regression test-day models.

    Science.gov (United States)

    Jamrozik, J; Bohmanova, J; Schaeffer, L R

    2010-04-01

    Using spline functions (segmented polynomials) in regression models requires the knowledge of the location of the knots. Knots are the points at which independent linear segments are connected. Optimal positions of knots for linear splines of different orders were determined in this study for different scenarios, using existing estimates of covariance functions and an optimization algorithm. The traits considered were test-day milk, fat and protein yields, and somatic cell score (SCS) in the first three lactations of Canadian Holsteins. Two ranges of days in milk (from 5 to 305 and from 5 to 365) were taken into account. In addition, four different populations of Holstein cows, from Australia, Canada, Italy and New Zealand, were examined with respect to first lactation (305 days) milk only. The estimates of genetic and permanent environmental covariance functions were based on single- and multiple-trait test-day models, with Legendre polynomials of order 4 as random regressions. A differential evolution algorithm was applied to find the best location of knots for splines of orders 4 to 7 and the criterion for optimization was the goodness-of-fit of the spline covariance function. Results indicated that the optimal position of knots for linear splines differed between genetic and permanent environmental effects, as well as between traits and lactations. Different populations also exhibited different patterns of optimal knot locations. With linear splines, different positions of knots should therefore be used for different effects and traits in random regression test-day models when analysing milk production traits.

  12. Implementing targeted expectant management in fertility care using prognostic modelling: a cluster randomized trial with a multifaceted strategy.

    Science.gov (United States)

    Kersten, F A M; Nelen, W L D M; van den Boogaard, N M; van Rumste, M M; Koks, C A; IntHout, J; Verhoeve, H R; Pelinck, M J; Boks, D E S; Gianotten, J; Broekmans, F J M; Goddijn, M; Braat, D D M; Mol, B W J; Hermens, R P G M

    2017-08-01

    What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline

  13. Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia

    Science.gov (United States)

    Lapalombella, Rosa; Sun, Qingxiang; Williams, Katie; Tangeman, Larissa; Jha, Shruti; Zhong, Yiming; Goettl, Virginia; Mahoney, Emilia; Berglund, Caroline; Gupta, Sneha; Farmer, Alicia; Mani, Rajeswaran; Johnson, Amy J.; Lucas, David; Mo, Xiaokui; Daelemans, Dirk; Sandanayaka, Vincent; Shechter, Sharon; McCauley, Dilara; Shacham, Sharon; Kauffman, Michael

    2012-01-01

    The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies. PMID:23034282

  14. Control of targeting ligand display by pH-responsive polymers on gold nanoparticles mediates selective entry into cancer cells.

    Science.gov (United States)

    Brazzale, C; Mastrotto, F; Moody, P; Watson, P D; Balasso, A; Malfanti, A; Mantovani, G; Caliceti, P; Alexander, C; Jones, A T; Salmaso, S

    2017-08-10

    Selective targeting of cells for intracellular delivery of therapeutics represents a major challenge for pharmaceutical intervention in disease. Here we show pH-triggered receptor-mediated endocytosis of nanoparticles via surface ligand exposure. Gold nanoparticles were decorated with two polymers: a 2 kDa PEG with a terminal folate targeting ligand, and a di-block copolymer including a pH-responsive and a hydrophilic block. At the normal serum pH of 7.4, the pH-responsive block (apparent pKa of 7.1) displayed a hydrophilic extended conformation, shielding the PEG-folate ligands, which inhibited cellular uptake of the nanoparticles. Under pH conditions resembling those of the extracellular matrix around solid tumours (pH 6.5), protonation of the pH-responsive polymer triggered a coil-to-globule polymer chain contraction, exposing folate residues on the PEG chains. In line with this, endocytosis of folate-decorated polymer-coated gold nanoparticles in cancer cells overexpressing folate receptor was significantly increased at pH 6.5, compared with pH 7.4. Thus, the tumour acidic environment and high folate receptor expression were effectively exploited to activate cell binding and endocytosis of these nanoparticles. These data provide proof-of-concept for strategies enabling extracellular pH stimuli to selectively enhance cellular uptake of drug delivery vectors and their associated therapeutic cargo.

  15. Targeted selective treatment for worm management--how do we sell rational programs to farmers?

    Science.gov (United States)

    van Wyk, J A; Hoste, H; Kaplan, R M; Besier, R B

    2006-07-31

    Seriously escalating global anthelmintic resistance in gastrointestinal nematodes of small ruminants has spawned a variety of alternatives to anthelmintics for worm management, based on the need for sustainable Integrated Parasite Management (sIPM). Pivotal to the sIPM approach is the concept of refugia, the proportion of a given parasite population that escapes exposure to control measures. By balancing drug applications with the maintenance of refugia, the accumulation of anthelmintic resistance alleles in worm populations can be considerably delayed, while still providing good levels of control. The over-dispersed nature of parasitic infections provides an opportunity to achieve this balance, by targeting treatments to the members of a flock or herd that are least tolerant to nematode infection. However, implementation of this strategy has only recently become feasible, with the development of the FAMACHA((c)) system for clinical evaluation of anaemia due to haemonchosis. Subsequently, the use of milk yields has proven an effective indicator in dairy goats infected predominantly with nematodes other than Haemonchus contortus. In addition, short-term weight changes and perhaps also body condition scoring may provide indices of parasitism, permitting the rapid identification of animals likely to benefit from treatment. However, sIPM and refugia-based approaches are more complex than whole-flock treatments in conventional programs, and adoption by farmers is most likely where the theoretical basis is understood. As close communication with informed advisors is generally limited, there is a danger that sIPM will remain a theoretical concept without alternative modes of communication. The development of computer-based decision support programs, which use epidemiological, seasonal and clinical information to provide recommendations for specific situations, should be accorded high priority in the future development of worm management systems.

  16. Development of a Genus-Specific Antigen Capture ELISA for Orthopoxviruses - Target Selection and Optimized Screening.

    Directory of Open Access Journals (Sweden)

    Daniel Stern

    Full Text Available Orthopoxvirus species like cowpox, vaccinia and monkeypox virus cause zoonotic infections in humans worldwide. Infections often occur in rural areas lacking proper diagnostic infrastructure as exemplified by monkeypox, which is endemic in Western and Central Africa. While PCR detection requires demanding equipment and is restricted to genome detection, the evidence of virus particles can complement or replace PCR. Therefore, an easily distributable and manageable antigen capture enzyme-linked immunosorbent assay (ELISA for the detection of orthopoxviruses was developed to facilitate particle detection. By comparing the virus particle binding properties of polyclonal antibodies developed against surface-exposed attachment or fusion proteins, the surface protein A27 was found to be a well-bound, highly immunogenic and exposed target for antibodies aiming at virus particle detection. Subsequently, eight monoclonal anti-A27 antibodies were generated and characterized by peptide epitope mapping and surface plasmon resonance measurements. All antibodies were found to bind with high affinity to two epitopes at the heparin binding site of A27, toward either the N- or C-terminal of the crucial KKEP-segment of A27. Two antibodies recognizing different epitopes were implemented in an antigen capture ELISA. Validation showed robust detection of virus particles from 11 different orthopoxvirus isolates pathogenic to humans, with the exception of MVA, which is apathogenic to humans. Most orthopoxviruses could be detected reliably for viral loads above 1 × 103 PFU/mL. To our knowledge, this is the first solely monoclonal and therefore reproducible antibody-based antigen capture ELISA able to detect all human pathogenic orthopoxviruses including monkeypox virus, except variola virus which was not included. Therefore, the newly developed antibody-based assay represents important progress towards feasible particle detection of this important genus of viruses.

  17. Development of a Genus-Specific Antigen Capture ELISA for Orthopoxviruses - Target Selection and Optimized Screening.

    Science.gov (United States)

    Stern, Daniel; Pauly, Diana; Zydek, Martin; Miller, Lilija; Piesker, Janett; Laue, Michael; Lisdat, Fred; Dorner, Martin B; Dorner, Brigitte G; Nitsche, Andreas

    2016-01-01

    Orthopoxvirus species like cowpox, vaccinia and monkeypox virus cause zoonotic infections in humans worldwide. Infections often occur in rural areas lacking proper diagnostic infrastructure as exemplified by monkeypox, which is endemic in Western and Central Africa. While PCR detection requires demanding equipment and is restricted to genome detection, the evidence of virus particles can complement or replace PCR. Therefore, an easily distributable and manageable antigen capture enzyme-linked immunosorbent assay (ELISA) for the detection of orthopoxviruses was developed to facilitate particle detection. By comparing the virus particle binding properties of polyclonal antibodies developed against surface-exposed attachment or fusion proteins, the surface protein A27 was found to be a well-bound, highly immunogenic and exposed target for antibodies aiming at virus particle detection. Subsequently, eight monoclonal anti-A27 antibodies were generated and characterized by peptide epitope mapping and surface plasmon resonance measurements. All antibodies were found to bind with high affinity to two epitopes at the heparin binding site of A27, toward either the N- or C-terminal of the crucial KKEP-segment of A27. Two antibodies recognizing different epitopes were implemented in an antigen capture ELISA. Validation showed robust detection of virus particles from 11 different orthopoxvirus isolates pathogenic to humans, with the exception of MVA, which is apathogenic to humans. Most orthopoxviruses could be detected reliably for viral loads above 1 × 103 PFU/mL. To our knowledge, this is the first solely monoclonal and therefore reproducible antibody-based antigen capture ELISA able to detect all human pathogenic orthopoxviruses including monkeypox virus, except variola virus which was not included. Therefore, the newly developed antibody-based assay represents important progress towards feasible particle detection of this important genus of viruses.

  18. The Endosymbiotic Bacterium Wolbachia Selectively Kills Male Hosts by Targeting the Masculinizing Gene.

    Directory of Open Access Journals (Sweden)

    Takahiro Fukui

    2015-07-01

    Full Text Available Pathogens are known to manipulate the reproduction and development of their hosts for their own benefit. Wolbachia is an endosymbiotic bacterium that infects a wide range of insect species. Wolbachia is known as an example of a parasite that manipulates the sex of its host's progeny. Infection of Ostrinia moths by Wolbachia causes the production of all-female progeny, however, the mechanism of how Wolbachia accomplishes this male-specific killing is unknown. Here we show for the first time that Wolbachia targets the host masculinizing gene of Ostrinia to accomplish male-killing. We found that Wolbachia-infected O. furnacalis embryos do not express the male-specific splice variant of doublesex, a gene which acts at the downstream end of the sex differentiation cascade, throughout embryonic development. Transcriptome analysis revealed that Wolbachia infection markedly reduces the mRNA level of Masc, a gene that encodes a protein required for both masculinization and dosage compensation in the silkworm Bombyx mori. Detailed bioinformatic analysis also elucidated that dosage compensation of Z-linked genes fails in Wolbachia-infected O. furnacalis embryos, a phenomenon that is extremely similar to that observed in Masc mRNA-depleted male embryos of B. mori. Finally, injection of in vitro transcribed Masc cRNA into Wolbachia-infected embryos rescued male progeny. Our results show that Wolbachia-induced male-killing is caused by a failure of dosage compensation via repression of the host masculinizing gene. Our study also shows a novel strategy by which a pathogen hijacks the host sex determination cascade.

  19. Targeting of breast metastases using a viral gene vector with tumour-selective transcription.

    LENUS (Irish Health Repository)

    Rajendran, Simon

    2012-01-31

    BACKGROUND: Adeno-associated virus (AAV) vectors have significant potential as gene delivery vectors for cancer gene therapy. However, broad AAV2 tissue tropism results in nonspecific gene expression. MATERIALS AND METHODS: We investigated use of the C-X-C chemokine receptor type 4 (CXCR4) promoter to restrict AAV expression to tumour cells, in subcutaneous MCF-7 xenograft mouse models of breast cancer and in patient samples, using bioluminescent imaging and flow cytometric analysis. RESULTS: Higher transgene expression levels were observed in subcutaneous MCF-7 tumours relative to normal tissue (muscle) using the CXCR4 promoter, unlike a ubiquitously expressing Cytomegalovirus promoter construct, with preferential AAVCXCR4 expression in epithelial tumour and CXCR4-positive cells. Transgene expression following intravenously administered AAVCXCR4 in a model of liver metastasis was detected specifically in livers of tumour bearing mice. Ex vivo analysis using patient samples also demonstrated higher AAVCXCR4 expression in tumour compared with normal liver tissue. CONCLUSION: This study demonstrates for the first time, the potential for systemic administration of AAV2 vector for tumour-selective gene therapy.

  20. Prey pursuit strategy of Japanese horseshoe bats during an in-flight target-selection task.

    Science.gov (United States)

    Kinoshita, Yuki; Ogata, Daiki; Watanabe, Yoshiaki; Riquimaroux, Hiroshi; Ohta, Tetsuo; Hiryu, Shizuko

    2014-09-01

    The prey pursuit behavior of Japanese horseshoe bats (Rhinolophus ferrumequinum nippon) was investigated by tasking bats during flight with choosing between two tethered fluttering moths. Echolocation pulses were recorded using a telemetry microphone mounted on the bat combined with a 17-channel horizontal microphone array to measure pulse directions. Flight paths of the bat and moths were monitored using two high-speed video cameras. Acoustical measurements of returning echoes from fluttering moths were first collected using an ultrasonic loudspeaker, turning the head direction of the moth relative to the loudspeaker from 0° (front) to 180° (back) in the horizontal plane. The amount of acoustical glints caused by moth fluttering varied with the sound direction, reaching a maximum at 70°-100° in the horizontal plane. In the flight experiment, moths chosen by the bat fluttered within or moved across these angles relative to the bat's pulse direction, which would cause maximum dynamic changes in the frequency and amplitude of acoustical glints during flight. These results suggest that echoes with acoustical glints containing the strongest frequency and amplitude modulations appear to attract bats for prey selection.

  1. Targeting procaspase-3 with WF-208, a novel PAC-1 derivative, causes selective cancer cell apoptosis.

    Science.gov (United States)

    Wang, Fangyang; Liu, Yajing; Wang, Lihui; Yang, Jingyu; Zhao, Yanfang; Wang, Nannan; Cao, Qi; Gong, Ping; Wu, Chunfu

    2015-08-01

    Caspase-3 is a critical effector caspase in apoptosis cascade, and is often over-expressed in many cancer tissues. The first synthesized procaspase-3 activator, PAC-1, induces cancer cell apoptosis and exhibits antitumour activity in murine xenograft models. To identify more potent procaspase-3 activators, a series of compounds were designed, synthesized and evaluated for their ability of inducing cancer cell death in culture. Among these compounds, WF-208 stood out by its high cytotoxicity against procaspase-3 overexpressed HL-60 cells. Compared with PAC-1, WF-208 showed higher cytotoxicity in cancer cells and lower toxicity in normal cells. The further investigation described herein showed that WF-208 activated procaspase-3, degraded IAPs (The Inhibitors of apoptosis proteins) and leaded to caspase-3-dependent cell death in tumour cells, which possibly because of the zinc-chelating properties. WF-208 also showed greater antitumour activity than PAC-1 in murine xenograft model. In conclusion, we have discovered WF-208 as a promising procaspase-3 activating compound, with higher activity and higher cell selectivity than PAC-1. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  2. Cost-effectiveness analysis of FET PET-guided target selection for the diagnosis of gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Heinzel, Alexander [Research Centre Juelich, Department of Nuclear Medicine of the Heinrich-Heine University of Duesseldorf, Juelich (Germany); Stock, Stephanie; Mueller, Dirk [University Hospital of Cologne, Institute for Health Economics and Clinical Epidemiology, Cologne (Germany); Langen, Karl-Josef [Research Centre Juelich, Institute for Neuroscience and Medicine 4, Juelich (Germany)

    2012-07-15

    Several diagnostic trials have indicated that the combined use of {sup 18}F-fluoroethyl-l-tyrosine (FET) PET and MRI may be superior to MRI alone in selecting the biopsy site for the diagnosis of gliomas. We estimated the cost-effectiveness of the use of amino acid PET compared to MRI alone from the perspective of the German statutory health insurance. To evaluate the incremental cost-effectiveness of the use of amino acid PET, a decision tree model was built. The effectiveness of FET PET was determined by the probability of a correct diagnosis. Costs were estimated for a baseline scenario and for a more expensive scenario in which disease severity was considered. The robustness of the results was tested using deterministic and probabilistic sensitivity analyses. The combined use of PET and MRI resulted in an increase of 18.5% in the likelihood of a correct diagnosis. The incremental cost-effectiveness ratio for one additional correct diagnosis using FET PET was EUR6,405 for the baseline scenario and EUR9,114 for the scenario based on higher disease severity. The probabilistic sensitivity analysis confirmed the robustness of the results. The model indicates that the use of amino acid PET may be cost-effective in patients with glioma. As a result of several limitations in the data used for the model, further studies are needed to confirm the results. (orig.)

  3. Visual working memory modulates low-level saccade target selection: evidence from rapidly generated saccades in the global effect paradigm.

    Science.gov (United States)

    Hollingworth, Andrew; Matsukura, Michi; Luck, Steven J

    2013-11-04

    In three experiments, we examined the influence of visual working memory (VWM) on the metrics of saccade landing position in a global effect paradigm. Participants executed a saccade to the more eccentric object in an object pair appearing on the horizontal midline, to the left or right of central fixation. While completing the saccade task, participants maintained a color in VWM for an unrelated memory task. Either the color of the saccade target matched the memory color (target match), the color of the distractor matched the memory color (distractor match), or the colors of neither object matched the memory color (no match). In the no-match condition, saccades tended to land at the midpoint between the two objects: the global, or averaging, effect. However, when one of the two objects matched VWM, the distribution of landing position shifted toward the matching object, both for target match and for distractor match. VWM modulation of landing position was observed even for the fastest quartile of saccades, with a mean latency as low as 112 ms. Effects of VWM on such rapidly generated saccades, with latencies in the express-saccade range, indicate that VWM interacts with the initial sweep of visual sensory processing, modulating perceptual input to oculomotor systems and thereby biasing oculomotor selection. As a result, differences in memory match produce effects on landing position similar to the effects generated by differences in physical salience.

  4. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

    Science.gov (United States)

    Janas, Maja M; Schlegel, Mark K; Harbison, Carole E; Yilmaz, Vedat O; Jiang, Yongfeng; Parmar, Rubina; Zlatev, Ivan; Castoreno, Adam; Xu, Huilei; Shulga-Morskaya, Svetlana; Rajeev, Kallanthottathil G; Manoharan, Muthiah; Keirstead, Natalie D; Maier, Martin A; Jadhav, Vasant

    2018-02-19

    Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

  5. Tumor cell-selective apoptosis induction through targeting of KV10.1 via bifunctional TRAIL antibody

    Science.gov (United States)

    2011-01-01

    Background The search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel KV10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins. Methods We designed a single-chain antibody against an extracellular region of KV10.1 (scFv62) and fused it to the human soluble TRAIL. The KV10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity. Results Prostate cancer cells, either positive or negative for KV10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in KV10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking KV10.1 expression. In co-cultures with KV10.1-positive cancer cells the fusion protein also induced apoptosis in bystander KV10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander. Conclusions KV10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a KV10.1-specific antibody. PMID:21899742

  6. Indirect targeting of IGF receptor signaling in vivo by substrate-selective inhibition of PAPP-A proteolytic activity

    Science.gov (United States)

    Kalra, Bhanu; Savjani, Gopal; Kumar, Ajay; Conover, Cheryl A.; Oxvig, Claus

    2014-01-01

    The insulin-like growth factor (IGF) signaling pathway is involved in certain human cancers, and the feasibility of directly targeting the IGF receptor has been actively investigated. However, recent evidence from clinical trials suggests that this approach can be problematic. We have developed an alternative strategy to indirectly inhibit the IGF signaling by targeting the metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). PAPP-A associated with the cell surface cleaves IGF binding protein-4 (IGFBP-4), when IGF is bound to IGFBP-4, and thereby increases IGF bioavailability for receptor activation in an autocrine/paracrine manner. We hypothesized that inhibition of PAPP-A would suppress excessive local IGF signaling in tissues where this is caused by increased PAPP-A proteolytic activity. To test this hypothesis, we developed an inhibitory monoclonal antibody, mAb 1/41, which targets a unique substrate-binding exosite of PAPP-A. This inhibitor selectively and specifically inhibits proteolytic cleavage of IGFBP-4 with an inhibitory constant (Ki) of 135 pM. In addition, it inhibited intracellular signaling of the IGF receptor (AKT phosphorylation) in monolayers of A549 cells, an IGF-responsive lung cancer-derived cell line found to express high levels of PAPP-A. We further showed that mAb 1/41 is effective towards PAPP-A bound to cell surfaces, and that it is capable of inhibiting PAPP-A activity in vivo. Using a murine xenograft model of A549 cells, we demonstrated that mAb 1/41 administered intraperitoneally significantly inhibited tumor growth. Analysis of xenograft tumor tissue recovered from treated mice showed penetration of mAb 1/41, reduced IGFBP-4 proteolysis, and reduced AKT phosphorylation. Our study provides proof of concept that IGF signaling can be selectively reduced by targeting a regulatory proteinase that functions extracellularly, upstream of the IGF receptor. PAPP-A targeting thus represents an alternative therapeutic strategy for

  7. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks.

    Science.gov (United States)

    Bilsland, Alan E; Pugliese, Angelo; Liu, Yu; Revie, John; Burns, Sharon; McCormick, Carol; Cairney, Claire J; Bower, Justin; Drysdale, Martin; Narita, Masashi; Sadaie, Mahito; Keith, W Nicol

    2015-09-01

    Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated β-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor-like profile in normal cells, with different pathways affected in cancer cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks

    Directory of Open Access Journals (Sweden)

    Alan E. Bilsland

    2015-09-01

    Full Text Available Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning–based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated β-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor–like profile in normal cells, with different pathways affected in cancer cells.

  9. Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters.

    Science.gov (United States)

    Gan, L; Xiu, R; Ren, P; Yue, M; Su, H; Guo, G; Xiao, D; Yu, J; Jiang, H; Liu, H; Hu, G; Qing, G

    2016-06-09

    Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.

  10. A Randomized Controlled Trial of Cognitive Debiasing Improves Assessment and Treatment Selection for Pediatric Bipolar Disorder

    Science.gov (United States)

    Jenkins, Melissa M.; Youngstrom, Eric A.

    2015-01-01

    Objective This study examined the efficacy of a new cognitive debiasing intervention in reducing decision-making errors in the assessment of pediatric bipolar disorder (PBD). Method The study was a randomized controlled trial using case vignette methodology. Participants were 137 mental health professionals working in different regions of the US (M=8.6±7.5 years of experience). Participants were randomly assigned to a (1) brief overview of PBD (control condition), or (2) the same brief overview plus a cognitive debiasing intervention (treatment condition) that educated participants about common cognitive pitfalls (e.g., base-rate neglect; search satisficing) and taught corrective strategies (e.g., mnemonics, Bayesian tools). Both groups evaluated four identical case vignettes. Primary outcome measures were clinicians’ diagnoses and treatment decisions. The vignette characters’ race/ethnicity was experimentally manipulated. Results Participants in the treatment group showed better overall judgment accuracy, p < .001, and committed significantly fewer decision-making errors, p < .001. Inaccurate and somewhat accurate diagnostic decisions were significantly associated with different treatment and clinical recommendations, particularly in cases where participants missed comorbid conditions, failed to detect the possibility of hypomania or mania in depressed youths, and misdiagnosed classic manic symptoms. In contrast, effects of patient race were negligible. Conclusions The cognitive debiasing intervention outperformed the control condition. Examining specific heuristics in cases of PBD may identify especially problematic mismatches between typical habits of thought and characteristics of the disorder. The debiasing intervention was brief and delivered via the Web; it has the potential to generalize and extend to other diagnoses as well as to various practice and training settings. PMID:26727411

  11. Slowing down fat digestion and absorption by an oxadiazolone inhibitor targeting selectively gastric lipolysis.

    Science.gov (United States)

    Point, Vanessa; Bénarouche, Anais; Zarrillo, Julie; Guy, Alexandre; Magnez, Romain; Fonseca, Laurence; Raux, Brigitt; Leclaire, Julien; Buono, Gérard; Fotiadu, Frédéric; Durand, Thierry; Carrière, Frédéric; Vaysse, Carole; Couëdelo, Leslie; Cavalier, Jean-François

    2016-11-10

    Based on a previous study and in silico molecular docking experiments, we have designed and synthesized a new series of ten 5-Alkoxy-N-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one derivatives (RmPPOX). These molecules were further evaluated as selective and potent inhibitors of mammalian digestive lipases: purified dog gastric lipase (DGL) and guinea pig pancreatic lipase related protein 2 (GPLRP2), as well as porcine (PPL) and human (HPL) pancreatic lipases contained in porcine pancreatic extracts (PPE) and human pancreatic juices (HPJ), respectively. These compounds were found to strongly discriminate classical pancreatic lipases (poorly inhibited) from gastric lipase (fully inhibited). Among them, the 5-(2-(Benzyloxy)ethoxy)-3-(3-PhenoxyPhenyl)-1,3,4-Oxadiazol-2(3H)-one (BemPPOX) was identified as the most potent inhibitor of DGL, even more active than the FDA-approved drug Orlistat. BemPPOX and Orlistat were further compared in vitro in the course of test meal digestion, and in vivo with a mesenteric lymph duct cannulated rat model to evaluate their respective impacts on fat absorption. While Orlistat inhibited both gastric and duodenal lipolysis and drastically reduced fat absorption in rats, BemPPOX showed a specific action on gastric lipolysis that slowed down the overall lipolysis process and led to a subsequent reduction of around 55% of the intestinal absorption of fatty acids compared to controls. All these data promote BemPPOX as a potent candidate to efficiently regulate the gastrointestinal lipolysis, and to investigate its link with satiety mechanisms and therefore develop new strategies to "fight against obesity". Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Impact of sleep inertia on visual selective attention for rare targets and the influence of chronotype.

    Science.gov (United States)

    Ritchie, Hannah K; Burke, Tina M; Dear, Tristan B; Mchill, Andrew W; Axelsson, John; Wright, Kenneth P

    2017-10-01

    Sleep inertia is affected by circadian phase, with worse performance upon awakening from sleep during the biological night than biological day. Visual search/selective visual attention performance is known to be sensitive to sleep inertia and circadian phase. Individual differences exist in the circadian timing of habitual wake time, which may contribute to individual differences in sleep inertia. Because later chronotypes awaken at an earlier circadian phase, we hypothesized that later chronotypes would have worse visual search performance during sleep inertia than earlier chronotypes if awakened at habitual wake time. We analysed performance from 18 healthy participants [five females (22.1 ± 3.7 years; mean ± SD)] at ~1, 10, 20, 30, 40 and 60 min following electroencephalogram-verified awakening from an 8 h in-laboratory sleep opportunity. Cognitive throughput and reaction times of correct responses were impaired by sleep inertia and took ~10-30 min to improve after awakening. Regardless whether chronotype was defined by dim light melatonin onset or mid-sleep clock hour on free days, derived from the Munich ChronoType Questionnaire, the duration of sleep inertia for cognitive throughput and reaction times was longer for later chronotypes (n = 7) compared with earlier chronotypes (n = 7). Specifically, performance for earlier chronotypes showed significant improvement within ~10-20 min after awakening, whereas performance for later chronotypes took ~30 min or longer to show significant improvement (P sleep, and are consistent with circadian theory suggesting that sleep inertia contributes to longer-lasting impairments in morning performance in later chronotypes. © 2017 European Sleep Research Society.

  13. BBB penetration-targeting physicochemical lead selection: Ecdysteroids as chemo-sensitizers against CNS tumors.

    Science.gov (United States)

    Müller, Judit; Martins, Ana; Csábi, József; Fenyvesi, Ferenc; Könczöl, Árpád; Hunyadi, Attila; Balogh, György T

    2017-01-01

    The anticancer potential of ecdysteroids, especially their chemo-sensitizing activity has recently gained a substantial scientific interest. A comprehensive physicochemical profiling was performed for a set of natural or semi-synthetic ecdysteroids (N=37) to identify a lead compound against central nervous system (CNS) tumors. Calculated properties, such as lipophilicity (clogP), topological polar surface area (TPSA), brain-to-plasma ratio (clogBB) along with the measured blood-brain barrier specific in vitro permeability (logPe) were evaluated in parallel. Compounds with the highest CNS-availability predicted (clogBB>0.0 and logPe>-6.0) showed moderate to high lipophilicity (clogP=3.89-5.25), relatively low TPSA (94.45Å2), and shared a common apolar 2,3- and 20,22-diacetonide motif (25, 30-33). These ecdysteroids were selected for testing their capacity to sensitize SH-SY5Y neuroblastoma cells to vincristine. All of the five tested compounds exerted a remarkably strong, dose dependent chemo-sensitizing activity: at 2.5-10.0μM ecdysteroids increased the cytotoxic activity of vincristine one to three orders of magnitude in (e.g., from IC50=39.5±2.9nM to as low as 0.056±0.03nM). Moreover, analysis of the combination index (CI) revealed outstanding synergism between ecdysteroids and vincristine (CI50=0.072-0.444). Thus, based on drug-likeness, physchem character and in vitro CNS activity, compound 25 was proposed as a lead for further in vivo studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Speech-language pathologists' practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders.

    Science.gov (United States)

    Mcleod, Sharynne; Baker, Elise

    2014-01-01

    A survey of 231 Australian speech-language pathologists (SLPs) was undertaken to describe practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders (SSD). The participants typically worked in private practice, education, or community health settings and 67.6% had a waiting list for services. For each child, most of the SLPs spent 10-40 min in pre-assessment activities, 30-60 min undertaking face-to-face assessments, and 30-60 min completing paperwork after assessments. During an assessment SLPs typically conducted a parent interview, single-word speech sampling, collected a connected speech sample, and used informal tests. They also determined children's stimulability and estimated intelligibility. With multilingual children, informal assessment procedures and English-only tests were commonly used and SLPs relied on family members or interpreters to assist. Common analysis techniques included determination of phonological processes, substitutions-omissions-distortions-additions (SODA), and phonetic inventory. Participants placed high priority on selecting target sounds that were stimulable, early developing, and in error across all word positions and 60.3% felt very confident or confident selecting an appropriate intervention approach. Eight intervention approaches were frequently used: auditory discrimination, minimal pairs, cued articulation, phonological awareness, traditional articulation therapy, auditory bombardment, Nuffield Centre Dyspraxia Programme, and core vocabulary. Children typically received individual therapy with an SLP in a clinic setting. Parents often observed and participated in sessions and SLPs typically included siblings and grandparents in intervention sessions. Parent training and home programs were more frequently used than the group therapy. Two-thirds kept up-to-date by reading journal articles monthly or every 6 months. There were many similarities with

  15. Genome-wide association data classification and SNPs selection using two-stage quality-based Random Forests.

    Science.gov (United States)

    Nguyen, Thanh-Tung; Huang, Joshua; Wu, Qingyao; Nguyen, Thuy; Li, Mark

    2015-01-01

    Single-nucleotide polymorphisms (SNPs) selection and identification are the most important tasks in Genome-wide association data analysis. The problem is difficult because genome-wide association data is very high dimensional and a large portion of SNPs in the data is irrelevant to the disease. Advanced machine learning methods have been successfully used in Genome-wide association studies (GWAS) for identification of genetic variants that have relatively big effects in some common, complex diseases. Among them, the most successful one is Random Forests (RF). Despite of performing well in terms of prediction accuracy in some data sets with moderate size, RF still suffers from working in GWAS for selecting informative SNPs and building accurate prediction models. In this paper, we propose to use a new two-stage quality-based sampling method in random forests, named ts-RF, for SNP subspace selection for GWAS. The method first applies p-value assessment to find a cut-off point that separates informative and irrelevant SNPs in two groups. The informative SNPs group is further divided into two sub-groups: highly informative and weak informative SNPs. When sampling the SNP subspace for building trees for the forest, only those SNPs from the two sub-groups are taken into account. The feature subspaces always contain highly informative SNPs when used to split a node at a tree. This approach enables one to generate more accurate trees with a lower prediction error, meanwhile possibly avoiding overfitting. It allows one to detect interactions of multiple SNPs with the diseases, and to reduce the dimensionality and the amount of Genome-wide association data needed for learning the RF model. Extensive experiments on two genome-wide SNP data sets (Parkinson case-control data comprised of 408,803 SNPs and Alzheimer case-control data comprised of 380,157 SNPs) and 10 gene data sets have demonstrated that the proposed model significantly reduced prediction errors and outperformed

  16. Role of selective V2-receptor-antagonism in septic shock: a randomized, controlled, experimental study

    OpenAIRE

    Rehberg, Sebastian; Ertmer, Christian; Lange, Matthias; Morelli, Andrea; Whorton, Elbert; Strohhäcker, Anne-Katrin; Dünser, Martin Wolfgang; Lipke, Erik; Kampmeier, Tim G; Aken, Hugo; Traber, Daniel L; Westphal, Martin

    2010-01-01

    ABSTRACT : INTRODUCTION : V2-receptor (V2R) stimulation potentially aggravates sepsis-induced vasodilation, fluid accumulation and microvascular thrombosis. Therefore, the present study was performed to determine the effects of a first-line therapy with the selective V2R-antagonist (Propionyl1-D-Tyr(Et)2-Val4-Abu6-Arg8,9)-Vasopressin on cardiopulmonary hemodynamics and organ function vs. the mixed V1aR/V2R-agonist arginine vasopressin (AVP) or placebo in an established ovine model of septic s...

  17. Ligand-Directed Functional Selectivity at the Mu Opioid Receptor Revealed by Label-Free Integrative Pharmacology On-Target

    Science.gov (United States)

    Morse, Megan; Tran, Elizabeth; Sun, Haiyan; Levenson, Robert; Fang, Ye

    2011-01-01

    Development of new opioid drugs that provide analgesia without producing dependence is important for pain treatment. Opioid agonist drugs exert their analgesia effects primarily by acting at the mu opioid receptor (MOR) sites. High-resolution differentiation of opioid ligands is crucial for the development of new lead drug candidates with better tolerance profiles. Here, we use a label-free integrative pharmacology on-target (iPOT) approach to characterize the functional selectivity of a library of known opioid ligands for the MOR. This approach is based on the ability to detect dynamic mass redistribution (DMR) arising from the activation of the MOR in living cells. DMR assays were performed in HEK-MOR cells with and without preconditioning with probe molecules using label-free resonant waveguide grating biosensors, wherein the probe molecules were used to modify the activity of specific signaling proteins downstream the MOR. DMR signals obtained were then translated into high resolution heat maps using similarity analysis based on a numerical matrix of DMR parameters. Our data indicate that the iPOT approach clearly differentiates functional selectivity for distinct MOR signaling pathways among different opioid ligands, thus opening new avenues to discover and quantify the functional selectivity of currently used and novel opioid receptor drugs. PMID:22003401

  18. In-vivo and in-vitro selective targeting of the retinal pigment epithelium using a laser-scanning device

    Science.gov (United States)

    Alt, Clemens; Framme, Carsten; Schnell, Susanne; Schuele, Georg; Brinkmann, Ralf; Lin, Charles P.

    2002-06-01

    Laser photocoagulation is a well-established treatment modality for a variety of retinal disorders, but is difficult to use near the fovea due to thermal retinal destruction. Certain diseases, such as drusen maculopathy, are thought to be caused by a dysfunction of the Retinal Pigment Epithelium. For those diseases selective targeting of the RPE, sparing the adjoining photoreceptors, might be the appropriate treatment to avoid laser scotoma, as it has been shown with application of a train of ms laser pulses by Birngruber and Roider. Our new approach is to use a conventional green cw laser and rapidly scan a small laser spot over the retina so as to produce microsecond(s) -illumination at each RPE cell. Two scanning devices were developed using acousto-optic deflectors. For the in vitro experiments the ED50 value RPE cell damage was 170 mW with 100 exposures, scanning with a speed of 1 spot diameter/3 microsecond(s) . In vivo experiments demonstrated an angiographic ED50 threshold of 66 mW for 100 exposures while scanning with an effective illumination time of 5 microsecond(s) . The ophthalmoscopic threshold was higher than a factor of 2 times the angiographic ED50. Using separated scan lines we show selectivity in the form of surviving cells in between irradiated lines. Selective destruction of RPE cells is possible using laser-scanning devices.

  19. Identification of effective treatment criteria for use in targeted selective treatment programs to control haemonchosis in periparturient ewes in Ontario, Canada.

    Science.gov (United States)

    Westers, T; Jones-Bitton, A; Menzies, P; VanLeeuwen, J; Poljak, Z; Peregrine, A S

    2016-11-01

    Haemonchosis is often associated with late gestation and parturition in ewes in Canada. Due to widespread concerns about development of anthelmintic resistance (AR), targeted selective treatment (TST), where individual animals are treated with an anthelmintic rather than the entire flock, is a possible strategy to control clinical signs in recently lambed ewes while still maintaining parasite refugia. Performing fecal egg counts (FEC) on individual animals is often cost-prohibitive, so indicators that identify ewes with high FEC are essential for TST programs. The study objectives were to: a) evaluate the ability of four TST indicators to identify periparturient ewes with high Haemonchus sp. FEC and b) determine appropriate treatment thresholds for statistically-significant indicators. A field study was conducted during the 2013 and 2014 lambing seasons (February-May) on three client-owned farms in Ontario with documented AR and problems with haemonchosis in ewes. Ewes were examined within three days of lambing and selected for treatment with oral closantel (10mg/kg body weight), a novel anthelmintic to Canada, if they met at least one of four criteria: a) the last grazing season was their first grazing season; b) body condition score ≤2; c) Faffa Malan Chart (FAMACHA©) score ≥3; and/or d) three or more nursing lambs. Fecal samples were collected per rectum on the treatment day from each of 20 randomly selected treated and untreated ewes on each farm. Haemonchus sp. percentages on each farm, as determined by coproculture, ranged from 53% to 92% of total fecal trichostrongyle-type egg counts. Mean Haemonchus sp. FECs were significantly higher in treated ewes (n=136) than in untreated ewes (n=103) on the day of treatment in both years (p=0.001), suggesting the indicators were suitable for identifying animals with high Haemonchus sp. FEC. A linear mixed model was fit with logarithmic-transformed Haemonchus sp. FEC as the outcome variable, the four indicators and

  20. Conflicts of Interest, Selective Inertia, and Research Malpractice in Randomized Clinical Trials: An Unholy Trinity.

    Science.gov (United States)

    Berger, Vance W

    2015-08-01

    Recently a great deal of attention has been paid to conflicts of interest in medical research, and the Institute of Medicine has called for more research into this important area. One research question that has not received sufficient attention concerns the mechanisms of action by which conflicts of interest can result in biased and/or flawed research. What discretion do conflicted researchers have to sway the results one way or the other? We address this issue from the perspective of selective inertia, or an unnatural selection of research methods based on which are most likely to establish the preferred conclusions, rather than on which are most valid. In many cases it is abundantly clear that a method that is not being used in practice is superior to the one that is being used in practice, at least from the perspective of validity, and that it is only inertia, as opposed to any serious suggestion that the incumbent method is superior (or even comparable), that keeps the inferior procedure in use, to the exclusion of the superior one. By focusing on these flawed research methods we can go beyond statements of potential harm from real conflicts of interest, and can more directly assess actual (not potential) harm.

  1. Participant-selected music and physical activity in older adults following cardiac rehabilitation: a randomized controlled trial.

    Science.gov (United States)

    Clark, Imogen N; Baker, Felicity A; Peiris, Casey L; Shoebridge, Georgie; Taylor, Nicholas F

    2017-03-01

    To evaluate effects of participant-selected music on older adults' achievement of activity levels recommended in the physical activity guidelines following cardiac rehabilitation. A parallel group randomized controlled trial with measurements at Weeks 0, 6 and 26. A multisite outpatient rehabilitation programme of a publicly funded metropolitan health service. Adults aged 60 years and older who had completed a cardiac rehabilitation programme. Experimental participants selected music to support walking with guidance from a music therapist. Control participants received usual care only. The primary outcome was the proportion of participants achieving activity levels recommended in physical activity guidelines. Secondary outcomes compared amounts of physical activity, exercise capacity, cardiac risk factors, and exercise self-efficacy. A total of 56 participants, mean age 68.2 years (SD = 6.5), were randomized to the experimental ( n = 28) and control groups ( n = 28). There were no differences between groups in proportions of participants achieving activity recommended in physical activity guidelines at Week 6 or 26. Secondary outcomes demonstrated between-group differences in male waist circumference at both measurements (Week 6 difference -2.0 cm, 95% CI -4.0 to 0; Week 26 difference -2.8 cm, 95% CI -5.4 to -0.1), and observed effect sizes favoured the experimental group for amounts of physical activity (d = 0.30), exercise capacity (d = 0.48), and blood pressure (d = -0.32). Participant-selected music did not increase the proportion of participants achieving recommended amounts of physical activity, but may have contributed to exercise-related benefits.

  2. Content analysis of a stratified random selection of JVME articles: 1974-2004.

    Science.gov (United States)

    Olson, Lynne E

    2011-01-01

    A content analysis was performed on a random sample (N = 168) of 25% of the articles published in the Journal of Veterinary Medical Education (JVME) per year from 1974 through 2004. Over time, there were increased numbers of authors per paper, more cross-institutional collaborations, greater prevalence of references or endnotes, and lengthier articles, which could indicate a trend toward publications describing more complex or complete work. The number of first authors that could be identified as female was greatest for the most recent time period studied (2000-2004). Two different categorization schemes were created to assess the content of the publications. The first categorization scheme identified the most frequently published topics as admissions, descriptions of courses, the effect of changing teaching methods, issues facing the profession, and examples of uses of technology. The second categorization scheme identified the subset of articles that described medical education research on the basis of the purpose of the research, which represented only 14% of the sample articles (24 of 168). Of that group, only three of 24, or 12%, represented studies based on a firm conceptual framework that could be confirmed or refuted by the study's results. The results indicate that JVME is meeting its broadly based mission and that publications in the veterinary medical education literature have features common to publications in medicine and medical education.

  3. Benefits of Selected Physical Exercise Programs in Detention: A Randomized Controlled Study

    Directory of Open Access Journals (Sweden)

    Claudia Battaglia

    2013-10-01

    Full Text Available The aim of the study was to determine which kind of physical activity could be useful to inmate populations to improve their health status and fitness levels. A repeated measure design was used to evaluate the effects of two different training protocols on subjects in a state of detention, tested pre- and post-experimental protocol.Seventy-five male subjects were enrolled in the studyand randomly allocated to three groups: the cardiovascular plus resistance training protocol group (CRT (n = 25; mean age 30.9 ± 8.9 years,the high-intensity strength training protocol group (HIST (n = 25; mean age 33.9 ± 6.8 years, and a control group (C (n = 25; mean age 32.9 ± 8.9 years receiving no treatment. All subjects underwent a clinical assessmentandfitness tests. MANOVA revealed significant multivariate effects on group (p < 0.01 and group-training interaction (p < 0.05. CRT protocol resulted the most effective protocol to reach the best outcome in fitness tests. Both CRT and HIST protocols produced significant gains in the functional capacity (cardio-respiratory capacity and cardiovascular disease risk decrease of incarcerated males. The significant gains obtained in functional capacity reflect the great potential of supervised exercise interventions for improving the health status of incarcerated people.

  4. The potential regimen of target-controlled infusion of propofol in flexible bronchoscopy sedation: a randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Ting-Yu Lin

    Full Text Available Target-controlled infusion (TCI provides precise pharmacokinetic control of propofol concentration in the effect-site (Ce, eg. brain. This pilot study aims to evaluate the feasibility and optimal TCI regimen for flexible bronchoscopy (FB sedation.After alfentanil bolus, initial induction Ce of propofol was targeted at 2 μg/ml. Patients were randomized into three titration groups (i.e., by 0.5, 0.2 and 0.1 μg/ml, respectively to maintain stable sedation levels and vital signs. Adverse events, frequency of adjustments, drug doses, and induction and recovery times were recorded.The study was closed early due to significantly severe hypoxemia events (oxyhemoglobin saturation <70% in the group titrated at 0.5 μg/ml. Forty-nine, 49 and 46 patients were enrolled into the 3 respective groups before study closure. The proportion of patients with hypoxemia events differed significantly between groups (67.3 vs. 46.9 vs. 41.3%, p = 0.027. Hypotension events, induction and recovery time and propofol doses were not different. The Ce of induction differed significantly between groups (2.4±0.5 vs. 2.1±0.4 vs. 2.1±0.3 μg/ml, p = 0.005 and the Ce of procedures was higher at 0.5 μg/ml titration (2.4±0.5 vs. 2.1±0.4 vs. 2.2±0.3 μg/ml, p = 0.006. The adjustment frequency tended to be higher for titration at 0.1 μg/ml but was not statistically significant (2 (0∼6 vs. 3 (0∼6 vs. 3 (0∼11. Subgroup analysis revealed 14% of all patients required no further adjustment during the whole sedation. Comparing patients requiring at least one adjustment with those who did not, they were observed to have a shorter induction time (87.6±34.9 vs. 226.9±147.9 sec, p<0.001, a smaller induction dose and Ce (32.5±4.1 vs. 56.8±22.7 mg, p<0.001; 1.76±0.17 vs. 2.28 ±0.41, p<0.001, respectively, and less hypoxemia and hypotension (15.8 vs.56.9%, p = 0.001; 0 vs. 24.1%, p = 0.008, respectively.Titration at 0.5 μg/ml is risky for FB sedation. A

  5. Bioactivity of compounds from Acmella oleracea against Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) and selectivity to two non-target species.

    Science.gov (United States)

    Moreno, Shaiene C; Carvalho, Geraldo A; Picanço, Marcelo C; Morais, Elisangela G F; Pereira, Rogério M

    2012-03-01

    Tropical plants are recognised sources of bioactive compounds that can be used for pest control. The objective of this study was to evaluate the biological activity of compounds present in Acmella oleracea (Asteracea) against Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), which is the main pest of tomato crops in Latin America. The selectivity of these compounds to the predator Solenopsis saevissima (Smith) (Hymenoptera: Formicidae) and to the pollinator Tetragonisca angustula (Latr.) (Hymenoptera: Apidae: Meliponinae) was also of interest. A bioassay screening with hexane and ethanol extracts from 23 plants was performed. The hexane extract of A. oleraceae was the most active of the extracts and was selected for further study. The following three alkamides were isolated from a hexane extract of the aerial parts of A. oleracea: spilanthol, (E)-N-isobutylundeca-2-en-8,10-diynamide and (R, E)-N-(2-methylbutyl)undeca-2-en-8,10-diynamide. All of the isolated compounds showed insecticidal activity, with spilanthol being the most active (LD(50) = 0.13 µg mg(-1) ) against T. absoluta. The alkamides were selective to both beneficial species studied. The crude hexane extract of A. oleraceae showed high insecticidal activity and can be used to control T. absoluta in organic or conventional crops. Quantification of LD(50) values of isolated compounds against T. absoluta showed that alkamides could serve as potent insecticides for T. absoluta control programmes. Spilanthol was the main alkamide active isolated. This alkamide is the most promising as it has the highest insecticidal activity and is selective to non-target organisms. Copyright © 2011 Society of Chemical Industry.

  6. Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

    Science.gov (United States)

    Schwartz, Brian; Garmey, Edward

    2011-01-01

    Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non–ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non–small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non–squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens. PMID:21632449

  7. Early clinical development of ARQ 197, a selective, non-ATP-competitive inhibitor targeting MET tyrosine kinase for the treatment of advanced cancers.

    Science.gov (United States)

    Adjei, Alex A; Schwartz, Brian; Garmey, Edward

    2011-01-01

    Expression of the receptor tyrosine kinase c-MET (MET, mesenchymal-epithelial transition factor) in many cancers, and its participation in multiple signal transduction pathways involved in malignant tumor growth, suggest a wide therapeutic potential for MET inhibition in human cancer. Here we describe the discovery and early clinical development of ARQ 197, a novel, selective, non-ATP-competitive inhibitor of MET. Phase I studies demonstrate that ARQ 197 has a predictable pharmacokinetics and favorable safety profile, making it a potentially ideal partner for combination with cytotoxic chemotherapies and targeted anticancer agents. Results from phase I and phase II trials demonstrate preliminary evidence of anticancer activity. New data from a global phase II randomized trial comparing a combination of ARQ 197 plus erlotinib with erlotinib/placebo, in endothelial growth factor receptor inhibitor-naïve patients with locally advanced/metastatic non-small cell lung cancer, demonstrate improvement in progression-free and overall survival with combined therapy. Results were especially pronounced for patients with non-squamous lung cancer histologies, and in particular molecularly defined subgroups including KRAS mutations. These and other data from ARQ 197 clinical trials in hepatocellular, germ-cell, pancreatic (in combination with gemcitabine), and colorectal (in combination with cetuximab and irinotecan) cancers further highlight the potential role of ARQ 197 in existing and emerging anticancer therapeutic regimens.

  8. Reduced plasma aldosterone concentrations in randomly selected patients with insulin-dependent diabetes mellitus.

    LENUS (Irish Health Repository)

    Cronin, C C

    2012-02-03

    Abnormalities of the renin-angiotensin system have been reported in patients with diabetes mellitus and with diabetic complications. In this study, plasma concentrations of prorenin, renin, and aldosterone were measured in a stratified random sample of 110 insulin-dependent (Type 1) diabetic patients attending our outpatient clinic. Fifty-four age- and sex-matched control subjects were also examined. Plasma prorenin concentration was higher in patients without complications than in control subjects when upright (geometric mean (95% confidence intervals (CI): 75.9 (55.0-105.6) vs 45.1 (31.6-64.3) mU I-1, p < 0.05). There was no difference in plasma prorenin concentration between patients without and with microalbuminuria and between patients without and with background retinopathy. Plasma renin concentration, both when supine and upright, was similar in control subjects, in patients without complications, and in patients with varying degrees of diabetic microangiopathy. Plasma aldosterone was suppressed in patients without complications in comparison to control subjects (74 (58-95) vs 167 (140-199) ng I-1, p < 0.001) and was also suppressed in patients with microvascular disease. Plasma potassium was significantly higher in patients than in control subjects (mean +\\/- standard deviation: 4.10 +\\/- 0.36 vs 3.89 +\\/- 0.26 mmol I-1; p < 0.001) and plasma sodium was significantly lower (138 +\\/- 4 vs 140 +\\/- 2 mmol I-1; p < 0.001). We conclude that plasma prorenin is not a useful early marker for diabetic microvascular disease. Despite apparently normal plasma renin concentrations, plasma aldosterone is suppressed in insulin-dependent diabetic patients.

  9. A Permutation Importance-Based Feature Selection Method for Short-Term Electricity Load Forecasting Using Random Forest

    Directory of Open Access Journals (Sweden)

    Nantian Huang

    2016-09-01

    Full Text Available The prediction accuracy of short-term load forecast (STLF depends on prediction model choice and feature selection result. In this paper, a novel random forest (RF-based feature selection method for STLF is proposed. First, 243 related features were extracted from historical load data and the time information of prediction points to form the original feature set. Subsequently, the original feature set was used to train an RF as the original model. After the training process, the prediction error of the original model on the test set was recorded and the permutation importance (PI value of each feature was obtained. Then, an improved sequential backward search method was used to select the optimal forecasting feature subset based on the PI value of each feature. Finally, the optimal forecasting feature subset was used to train a new RF model as the final prediction model. Experiments showed that the prediction accuracy of RF trained by the optimal forecasting feature subset was higher than that of the original model and comparative models based on support vector regression and artificial neural network.

  10. Selection of focal earthworm species as non-target soil organisms for environmental risk assessment of genetically modified plants.

    Science.gov (United States)

    van Capelle, Christine; Schrader, Stefan; Arpaia, Salvatore

    2016-04-01

    By means of a literature survey, earthworm species of significant relevance for soil functions in different biogeographical regions of Europe (Atlantic, Boreal, Mediterranean) were identified. These focal earthworm species, defined here according to the EFSA Guidance Document on the environmental risk assessment (ERA) of genetically modified plants, are typical for arable soils under crop rotations with maize and/or potatoes within the three regions represented by Ireland, Sweden and Spain, respectively. Focal earthworm species were selected following a matrix of four steps: Identification of functional groups, categorization of non-target species, ranking species on ecological criteria, and final selection of focal species. They are recommended as appropriate non-target organisms to assess environmental risks of genetically modified (GM) crops; in this case maize and potatoes. In total, 44 literature sources on earthworms in arable cropping systems including maize or potato from Ireland, Sweden and Spain were collected, which present information on species diversity, individual density and specific relevance for soil functions. By means of condensed literature data, those species were identified which (i) play an important functional role in respective soil systems, (ii) are well adapted to the biogeographical regions, (iii) are expected to occur in high abundances under cultivation of maize or potato and (iv) fulfill the requirements for an ERA test system based on life-history traits. First, primary and secondary decomposers were identified as functional groups being exposed to the GM crops. In a second step, anecic and endogeic species were categorized as potential species. In step three, eight anecic and endogeic earthworm species belonging to the family Lumbricidae were ranked as relevant species: Aporrectodea caliginosa, Aporrectodea rosea, Aporrectodea longa, Allolobophora chlorotica, Lumbricus terrestris, Lumbricus friendi, Octodrilus complanatus and

  11. Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T.

    Science.gov (United States)

    Streng, Alexander S; de Boer, Douwe; Bouwman, Freek G; Mariman, Edwin C M; Scholten, Arjen; van Dieijen-Visser, Marja P; Wodzig, Will K W H

    2016-03-16

    Cardiac troponin T (cTnT) is a highly cardiospecific protein commonly used in the diagnosis of acute myocardial infarction (AMI), but is subject to proteolytic degradation upon its release in the circulation. In this study, a targeted mass spectrometry assay was developed to detect peptides which are differentially present within the different degradation products. cTnT was spiked in human serum and incubated at 37 °C to induce proteolytic degradation. Isolation and fractionation of cTnT and its fragments from serum were performed using immunoprecipitation and SDS-PAGE. Bands migrating to 37 kDa (intact cTnT), 29 kDa (primary fragment), and 19, 18, and 16kDa (secondary fragments) were excised, digested, and subsequently analysed using targeted selected ion monitoring on a UHPLC-coupled quadrupole-Orbitrap mass spectrometer. Sixteen precursor ions from a total of 11 peptides unique to cTnT were targeted. Precursor ions were detectable up until 1200 ng/L cTnT, which is a typical cTnT concentration after AMI. With tandem-MS and relative quantification, we proved the formation of cTnT fragments upon incubation in human serum and identified differentially present peptides in the fragment bands, indicative of N- and C-terminal proteolytic cleavage. These findings are of importance for the development of future cTnT assays, calibrators, and quality control samples. In this study we have developed a gel-based targeted mass spectrometry assay which is able to differentiate between different molecular forms of cTnT. The unravelling of the molecular presentation of cTnT in human serum is of importance in the field of clinical chemistry, where this highly specific and sensitive biomarker is being measured on a routinely basis in patient samples. Knowledge of the amino acid sequence of the different cTnT fragments may aid in the development of improved calibrators and quality control samples. In addition, different fragmentation patterns may be indicative of different

  12. Mixed methods evaluation of targeted selective anthelmintic treatment by resource-poor smallholder goat farmers in Botswana.

    Science.gov (United States)

    Walker, Josephine G; Ofithile, Mphoeng; Tavolaro, F Marina; van Wyk, Jan A; Evans, Kate; Morgan, Eric R

    2015-11-30

    Due to the threat of anthelmintic resistance, livestock farmers worldwide are encouraged to selectively apply treatments against gastrointestinal nematodes (GINs). Targeted selective treatment (TST) of individual animals would be especially useful for smallholder farmers in low-income economies, where cost-effective and sustainable intervention strategies will improve livestock productivity and food security. Supporting research has focused mainly on refining technical indicators for treatment, and much less on factors influencing uptake and effectiveness. We used a mixed method approach, whereby qualitative and quantitative approaches are combined, to develop, implement and validate a TST system for GINs in small ruminants, most commonly goats, among smallholder farmers in the Makgadikgadi Pans region of Botswana, and to seek better understanding of system performance within a cultural context. After the first six months of the study, 42 out of 47 enrolled farmers were followed up; 52% had monitored their animals using the taught inspection criteria and 26% applied TST during this phase. Uptake level showed little correlation with farmer characteristics, such as literacy and size of farm. Herd health significantly improved in those herds where anthelmintic treatment was applied: anaemia, as assessed using the five-point FAMACHA(©) scale, was 0.44-0.69 points better (95% confidence interval) and body condition score was 0.18-0.36 points better (95% C.I., five-point scale) in treated compared with untreated herds. Only targeting individuals in greatest need led to similar health improvements compared to treating the entire herd, leading to dose savings ranging from 36% to 97%. This study demonstrates that TST against nematodes can be implemented effectively by resource-poor farmers using a community-led approach. The use of mixed methods provides a promising system to integrate technical and social aspects of TST programmes for maximum uptake and effect. Copyright

  13. Mesoscale Assessment of CO2 Storage Potential and Geological Suitability for Target Area Selection in the Sichuan Basin

    Directory of Open Access Journals (Sweden)

    Yujie Diao

    2017-01-01

    Full Text Available In China, south of the Yangtze River, there are a large number of carbon sources, while the Sichuan Basin is the largest sedimentary basin; it makes sense to select the targets for CO2 geological storage (CGUS early demonstration. For CO2 enhanced oil and gas, coal bed methane recovery (CO2-EOR, EGR, and ECBM, or storage in these depleted fields, the existing oil, gas fields, or coal seams could be the target areas in the mesoscale. This paper proposed a methodology of GIS superimposed multisource information assessment of geological suitability for CO2 enhanced water recovery (CO2-EWR or only storage in deep saline aquifers. The potential per unit area of deep saline aquifers CO2 storage in Central Sichuan is generally greater than 50 × 104 t/km2 at P50 probability level, with Xujiahe group being the main reservoir. CO2 storage potential of depleted gas fields is 53.73 × 108 t, while it is 33.85 × 108 t by using CO2-EGR technology. This paper recommended that early implementation of CGUS could be carried out in the deep saline aquifers and depleted gas fields in the Sichuan Basin, especially that of the latter because of excellent traps, rich geological data, and well-run infrastructures.

  14. Practices to optimise gastrointestinal nematode control on sheep, goat and cattle farms in Europe using targeted (selective) treatments.

    Science.gov (United States)

    Charlier, J; Morgan, E R; Rinaldi, L; van Dijk, J; Demeler, J; Höglund, J; Hertzberg, H; Van Ranst, B; Hendrickx, G; Vercruysse, J; Kenyon, F

    2014-09-13

    Due to the development of anthelmintic resistance, there have been calls for more sustainable nematode control practices. Two important concepts were introduced to study and promote the sustainable use of anthelmintics: targeted treatments (TT), where the whole flock/herd is treated based on knowledge of the risk, or parameters that quantify the severity of infection; and targeted selective treatments (TST), where only individual animals within the grazing group are treated. The aim of the TT and TST approaches is to effectively control nematode-induced production impacts while preserving anthelmintic efficacy by maintaining a pool of untreated parasites in refugia. Here, we provide an overview of recent studies that assess the use of TT/TST against gastrointestinal nematodes in ruminants and investigate the economic consequences, feasibility and knowledge gaps associated with TST. We conclude that TT/TST approaches are ready to be used and provide practical benefits today. However, a major shift in mentality will be required to make these approaches common practice in parasite control. British Veterinary Association.

  15. Preference option randomized design (PORD) for comparative effectiveness research: Statistical power for testing comparative effect, preference effect, selection effect, intent-to-treat effect, and overall effect.

    Science.gov (United States)

    Heo, Moonseong; Meissner, Paul; Litwin, Alain H; Arnsten, Julia H; McKee, M Diane; Karasz, Alison; McKinley, Paula; Rehm, Colin D; Chambers, Earle C; Yeh, Ming-Chin; Wylie-Rosett, Judith

    2017-01-01

    Comparative effectiveness research trials in real-world settings may require participants to choose between preferred intervention options. A randomized clinical trial with parallel experimental and control arms is straightforward and regarded as a gold standard design, but by design it forces and anticipates the participants to comply with a randomly assigned intervention regardless of their preference. Therefore, the randomized clinical trial may impose impractical limitations when planning comparative effectiveness research trials. To accommodate participants' preference if they are expressed, and to maintain randomization, we propose an alternative design that allows participants' preference after randomization, which we call a "preference option randomized design (PORD)". In contrast to other preference designs, which ask whether or not participants consent to the assigned intervention after randomization, the crucial feature of preference option randomized design is its unique informed consent process before randomization. Specifically, the preference option randomized design consent process informs participants that they can opt out and switch to the other intervention only if after randomization they actively express the desire to do so. Participants who do not independently express explicit alternate preference or assent to the randomly assigned intervention are considered to not have an alternate preference. In sum, preference option randomized design intends to maximize retention, minimize possibility of forced assignment for any participants, and to maintain randomization by allowing participants with no or equal preference to represent random assignments. This design scheme enables to define five effects that are interconnected with each other through common design parameters-comparative, preference, selection, intent-to-treat, and overall/as-treated-to collectively guide decision making between interventions. Statistical power functions for testing

  16. Optimal Systolic Blood Pressure Target After SPRINT: Insights from a Network Meta-Analysis of Randomized Trials.

    Science.gov (United States)

    Bangalore, Sripal; Toklu, Bora; Gianos, Eugenia; Schwartzbard, Arthur; Weintraub, Howard; Ogedegbe, Gbenga; Messerli, Franz H

    2017-06-01

    The optimal on-treatment blood pressure (BP) target has been a matter of debate. The recent SPRINT trial showed significant benefits of a BP target of meta-analysis. Seventeen trials that enrolled 55,163 patients with 204,103 patient-years of follow-up were included. There was a significant decrease in stroke (rate ratio [RR] 0.54; 95% confidence interval [CI], 0.29-1.00) and myocardial infarction (RR 0.68; 95% CI, 0.47-1.00) with systolic BP <120 mm Hg (vs <160 mm Hg). Sensitivity analysis using achieved systolic BP showed a 72%, 97%, and 227% increase in stroke with systolic BP of <140 mm Hg, <150 mm Hg, and <160 mm, respectively, when compared with systolic BP <120 mm Hg. There was no difference in death, cardiovascular death, or heart failure when comparing any of the BP targets. However, the point estimate favored lower BP targets (<120 mm Hg, <130 mm Hg) when compared with higher BP targets (<140 mm Hg or <150 mm Hg). BP targets of <120 mm Hg and <130 mm Hg ranked #1 and #2, respectively, as the most efficacious target. There was a significant increase in serious adverse effects with systolic BP <120 mm Hg vs <150 mm Hg (RR 1.83; 95% CI, 1.05-3.20) or vs <140 mm Hg (RR 2.12; 95% CI, 1.46-3.08). BP targets of <140 mm Hg and <150 mm Hg ranked #1 and #2, respectively, as the safest target for the outcome of serious adverse effects. Cluster plots for combined efficacy and safety showed that a systolic BP target of <130 mm Hg had optimal balance between efficacy and safety. In patients with hypertension, a on-treatment systolic BP target of <130 mm Hg achieved optimal balance between efficacy and safety. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Single-chain lipopeptide vaccines for the induction of virus-specific cytotoxic T cell responses in randomly selected populations.

    Science.gov (United States)

    Gras-Masse, H

    2001-12-01

    Effective vaccine development is now taking advantage of the rapidly accumulating information concerning the molecular basis of a protective immune response. Analysts and medicinal chemists have joined forces with immunologists and taken up the clear challenge of identifying immunologically active structural elements and synthesizing them in pure, reproducible forms. Current literature reveals the growing interest for extremely reductionist approaches aiming at producing totally synthetic vaccines that would be fully defined at the molecular level and particularly safe. The sequential information contained in these formulations tends to be minimized to those epitopes which elicit neutralizing antibodies, or cell-mediated responses. In the following review, we describe some of our results in developing fully synthetic, clinically acceptable lipopeptide vaccines for inducing cytotoxic T lymphocytes (CTL) responses in randomly selected populations.